Activity Of Auditory Nerve Fibers Research Articles

Development of a feline model for preclinical research of a new translabyrinthine auditory nerve implant.

Cochlear implants are among the most successful neural prosthetic devices to date but exhibit poor frequency selectivity and the inability to consistently activate apical (low frequency) spiral ganglion neurons. These issues can limit hearing performance in many cochlear implant patients, especially for understanding speech in noisy environments and in perceiving or appreciating more complex inputs such as music and multiple talkers. For cochlear implants, electrical current must pass through the bony wall of the cochlea, leading to widespread activation of auditory nerve fibers. Cochlear implants also cannot be implanted in some individuals with an obstruction or severe malformations of the cochlea. Alternatively, intraneural stimulation delivered via an auditory nerve implant could provide direct contact with neural fibers and thus reduce unwanted current spread. More confined current during stimulation can increase selectivity of frequency fiber activation. Furthermore, devices such as the Utah Slanted Electrode Array can provide access to the full cross section of the auditory nerve, including low frequency fibers that are difficult to reach using a cochlear implant. However, further scientific and preclinical research of these Utah Slanted Electrode Array devices is limited by the lack of a chronic large animal model for the auditory nerve implant, especially one that leverages an appropriate surgical approach relevant for human translation. This paper presents a newly developed transbullar translabyrinthine surgical approach for implanting the auditory nerve implant into the cat auditory nerve. In our first of a series of studies, we demonstrate a surgical approach in non-recovery experiments that enables implantation of the auditory nerve implant into the auditory nerve, without damaging the device and enabling effective activation of the auditory nerve fibers, as measured by electrode impedances and electrically evoked auditory brainstem responses. These positive results motivate performing future chronic cat studies to assess the long-term stability and function of these auditory nerve implant devices, as well as development of novel stimulation strategies that can be translated to human patients.

Cochlear aging disrupts the correlation between spontaneous rate- and sound-level coding in auditory nerve fibers.

The spiking activity of auditory nerve fibers (ANFs) transmits information about the acoustic environment from the cochlea to the central auditory system. Increasing age leads to degeneration of cochlear tissues, including the sensory hair cells and stria vascularis. Here, we aim to identify the functional effects of such age-related cochlear pathologies of ANFs. Rate-level functions (RLFs) were recorded from single-unit ANFs of young adult (n = 52, 3-12 months) and quiet-aged (n = 24, >36 months) Mongolian gerbils of either sex. RLFs were used to determine sensitivity and spontaneous rates (SRs) and were classified into flat-saturating, sloping-saturating, and straight categories, as previously established. A physiologically based cochlear model, adapted for the gerbil, was used to simulate the effects of cochlear degeneration on ANF physiology. In ANFs tuned to low frequencies (<3.5 kHz), SR was lower in those of aged gerbils, while an age-related loss of low-SR fibers was evident in ANFs tuned to high frequencies. These changes in SR distribution did not affect the typical SR versus sensitivity correlation. The distribution of RLF types among low-SR fibers, however, shifted toward that of high-SR fibers, specifically showing more fast-saturating and fewer sloping-saturating RLFs. A modeled striatal degeneration, which affects the combined inner hair cell and synaptic output, reduced SR but left RLF type unchanged. An additional reduced basilar membrane gain, which decreased sensitivity, explained the changed RLF types. Overall, the data indicated age-related changes in the characteristics of single ANFs that blurred the established relationships between SR and RLF types.NEW & NOTEWORTHY Auditory nerve fibers, which connect the cochlea to the central auditory system, change their encoding of sound level in aged gerbils. In addition to a general shift to higher levels, indicative of decreased sensitivity, level coding was also differentially affected in fibers with low- and high-spontaneous rates. Loss of low-spontaneous rate fibers, combined with a general decrease of spontaneous rate, further blurs the categorization of auditory nerve fiber types in the aged gerbil.

What Is the Benefit of Ramped Pulse Shapes for Activating Auditory Cortex Neurons? An Electrophysiological Study in an Animal Model of Cochlear Implant.

In all commercial cochlear implant (CI) devices, the activation of auditory nerve fibers is performed with rectangular pulses that have two phases of opposite polarity. Recently, several papers proposed that ramped pulse shapes could be an alternative shape for efficiently activating auditory nerve fibers. Here, we investigate whether ramped pulse shapes can activate auditory cortex (ACx) neurons in a more efficient way than the classical rectangular pulses. Guinea pigs were implanted with CI devices and responses of ACx neurons were tested with rectangular pulses and with four ramped pulse shapes, with a first-phase being either cathodic or anodic. The thresholds, i.e., the charge level necessary for obtaining significant cortical responses, were almost systematically lower with ramped pulses than with rectangular pulses. The maximal firing rate (FR) elicited by the ramped pulses was higher than with rectangular pulses. As the maximal FR occurred with lower charge levels, the dynamic range (between threshold and the maximal FR) was not modified. These effects were obtained with cathodic and anodic ramped pulses. By reducing the charge levels required to activate ACx neurons, the ramped pulse shapes should reduce charge consumption and should contribute to more battery-efficient CI devices in the future.

Physiopathological Relevance of D-Serine in the Mammalian Cochlea

NMDA receptors (NMDARs) populate the complex between inner hair cell (IHC) and spiral ganglion neurons (SGNs) in the developing and mature cochlea. However, in the mature cochlea, activation of NMDARs is thought to mainly occur under pathological conditions such as excitotoxicity. Ototoxic drugs such as aspirin enable cochlear arachidonic-acid-sensitive NMDAR responses, and induced chronic tinnitus was blocked by local application of NMDAR antagonists into the cochlear fluids. We largely ignore if other modulators are also engaged. In the brain, D-serine is the primary physiological co-agonist of synaptic NMDARs. Whether D-serine plays a role in the cochlea had remained unexplored. We now reveal the presence of D-serine and its metabolic enzymes prior to, and at hearing onset, in the sensory and non-neuronal cells of the cochlea of several vertebrate species. In vivo intracochlear perfusion of D-serine in guinea pigs reduces sound-evoked activity of auditory nerve fibers without affecting the receptor potentials, suggesting that D-serine acts specifically on the postsynaptic auditory neurons without altering the functional state of IHC or of the stria vascularis. Indeed, we demonstrate in vitro that agonist-induced activation of NMDARs produces robust calcium responses in rat SGN somata only in the presence of D-serine, but not of glycine. Surprisingly, genetic deletion in mice of serine racemase (SR), the enzyme that catalyzes D-serine, does not affect hearing function, but offers protection against noise-induced permanent hearing loss as measured 3 months after exposure. However, the mechanisms of activation of NMDA receptors in newborn rats may be different from those in adult guinea pigs. Taken together, these results demonstrate for the first time that the neuro-messenger D-serine has a pivotal role in the cochlea by promoting the activation of silent cochlear NMDAR in pathological situations. Thus, D-serine and its signaling pathway may represent a new druggable target for treating sensorineural hearing disorders (i.e., hearing loss, tinnitus).

Sound exposure dynamically induces dopamine synthesis in cholinergic LOC efferents for feedback to auditory nerve fibers.

Lateral olivocochlear (LOC) efferent neurons modulate auditory nerve fiber (ANF) activity using a large repertoire of neurotransmitters, including dopamine (DA) and acetylcholine (ACh). Little is known about how individual neurotransmitter systems are differentially utilized in response to the ever-changing acoustic environment. Here we present quantitative evidence in rodents that the dopaminergic LOC input to ANFs is dynamically regulated according to the animal's recent acoustic experience. Sound exposure upregulates tyrosine hydroxylase, an enzyme responsible for dopamine synthesis, in cholinergic LOC intrinsic neurons, suggesting that individual LOC neurons might at times co-release ACh and DA. We further demonstrate that dopamine down-regulates ANF firing rates by reducing both the hair cell release rate and the size of synaptic events. Collectively, our results suggest that LOC intrinsic neurons can undergo on-demand neurotransmitter re-specification to re-calibrate ANF activity, adjust the gain at hair cell/ANF synapses, and possibly to protect these synapses from noise damage.

Sound localization by the internally coupled ears of lizards: From biophysics to biorobotics.

As they are generally small and only hear low frequencies, lizards have few cues for localizing sound. However, their ears show extreme directionality (up to 30 dB direction-dependent difference in eardrum vibrations) created by strong acoustical coupling of the eardrums, with almost perfect internal transmission from the contralateral ear over a broad frequency range. The activity of auditory nerve fibers reflects the eardrum directionality, so all auditory neurons are directional by default. This suggests that the ensuing neural processing of sound direction is simple in lizards. Even the simplest configuration of electrical analog models-two tympanic impedances connected via a central capacitor-produces directional patterns that are qualitatively similar to the experimental data on lizard ears. Several models, both analytical and (very recently) finite-element models, have been published. Robotic implementations using simplified models of the ear and of binaural comparison show that robust phonotaxic behavior can be generated with little additional processing and be performed by simple (and thus small and cheap) units. The authors review lizard directional processing and attempts at modeling and robotics with a twofold aim: to clarify the authors' understanding of central processing of sound localization in lizards, and to lead to technological developments of bioinspired robotics.

Amplitude Modulation May Be Confused with Infrasound

Environmental infrasound is usually accompanied by low-frequency (LF) sounds. Considering that inner hair cell transduction equals half-wave rectification, activity of low-frequency auditory nerve fibres may be indistinguishable whether elicited by LF sound that is amplitude-modulated at an infrasonic rate, or LF sound that is superimposed onto infrasound that biases the basilar membrane position. We tested whether listeners are able to distinguish a 63-Hz carrier tone, amplitude modulated at 8 Hz, from a 63-Hz pure tone that was perceptually loudness-modulated by an 8-Hz biasing tone. Using a maximum-likelihood procedure, 12 participants first adjusted the intensity of the 8-Hz tone so that the perceived modulation of the pure tone matched a reference amplitude-modulated tone. Both stimuli types were then presented in random order, and participants had to identify presentations which contained the infrasound tone. About half the participants performed close to chance. The best had 81% correct. Experiments with a 125-Hz carrier tone gave similar results. Although performance may improve in a 2-interval discrimination task, this would not be representative of real listening conditions. Results suggest that slowly amplitude-modulated LF sounds may underlie complaints about environmental infrasound, where measured infrasound levels are well below sensation threshold.

Recovery of auditory-nerve-fiber spike amplitude under natural excitation conditions

Knowledge of the refractory properties of auditory-nerve fibers (ANFs) is required for understanding the transduction of the graded membrane potential of the receptor cells into spike trains. The refractory properties inferred when ANFs are excited by electrical stimulation might differ from those present when ANFs are excited naturally by transmitter release from receptor cells. As a proxy for the latter, we investigated the recovery of spike amplitude with time since the previous spike in long extracellular recordings of the activity of individual ANFs from anesthetized Mongolian gerbils. Voltage traces were filtered minimally to avoid distortions of spike amplitude and timing. The amplitude of each spike was defined as the difference between its peak voltage and an extrapolated instantaneous reference voltage at the time of the peak. Spike amplitude was normalized to that of the previous spike to exclude effects of long-term changes in recording conditions. To ensure that the amplitude of the first spike in each pair was fully recovered, each spike pair was used only when preceded by an interspike interval of at least 5 ms. We find that the recovery of spike amplitude is well described by a short dead time followed by a double-exponential recovery function. Total recovery times were short (median: 0.85 ms; interquartile range: 0.74–1.00 ms) and independent of the ANF's characteristic frequency and spontaneous rate, but they increased weakly with increasing mean rate. We emphasize the differences between the recovery of spike amplitude, the recovery of spike probability from postsynaptic refractoriness, and the recovery of spike probability as reflected in the hazard-rate function. Our findings are inconsistent with the long refractory periods assumed in some models, but are consistent with the brief refractoriness assumed in the synapse model of Peterson and Heil (2018), which reproduces the stochastic properties of stationary spontaneous and sound-driven ANF spike trains.

Cochlear Implant - State of the Art

Cochlear implants are the treatment of choice for the auditory rehabilitation of patients with sensory deafness. They restore the missing function of inner hair cells by transforming the acoustic signal into electrical stimuli for activation of auditory nerve fibers. Due to the very fast technology development cochlear implants provide open-set speech understanding in the majority of patients including the use of the telephone. Children can achieve a near to normal speech and language development provided their deafness is detected early after onset and implantation is performed quickly thereafter. The diagnostic procedure as well as the surgical techniques have been standardized and can be adapted to the individual anatomical and physiological needs both in children and adults. Special cases such as cochlear obliteration or malformations can be addressed. Device failures and medical complications might require special measures and reimplantation which can be done in most cases in a straight forward way. Technology upgrades count for better performance.Future developments will focus on better electrode nerve interfaces by improving electrode technology. An increased number of electrical contacts as well as the biological treatment with regeneration of the dendrides growing onto the electrode will increase the number of electrical channels. This will give room for improved speech coding strategies in order to create the bionic ear, i. e. to restore the process of natural hearing by means of technology. The robot assisted surgery will allow for high precision surgery and reliable hearing preservation. Biological therapies will support the bionic ear. Methods are biohybrid electrodes which are coded by stem cells transplanted into the inner ear to enhance autoproduction of neurotrophins. Local drug delivery will focus on suppression of trauma reaction and local regeneration. Gene therapy by nanoparticles will hopefully lead to the preservation of residual hearing in patients being affected by genetic hearing loss. Overall the cochlear implant is a very powerful tool to rehabilitate patients with sensory deafness. More than 1 million of candidates in Germany today could benefit from this high technology auditory implant. Only 50,000 are implanted so far. In the future the procedure can be done under local anesthesia, will be minimal invasive and straight forward. Hearing preservation will be routine.

Mass Potentials Recorded at the Round Window Enable the Detection of Low Spontaneous Rate Fibers in Gerbil Auditory Nerve.

Auditory nerve fibers (ANFs) transmit acoustic information from the sensory hair cells to the cochlear nuclei. In experimental and clinical audiology, probing the whole ANF population remains a difficult task, as the ANFs differ greatly in their threshold and onset response to sound. Thus, low spontaneous rate (SR) fibers, which have rather higher thresholds, delay and larger jitter in their first spike latency are not detectable in the far-field compound action potential of the auditory nerve. Here, we developed a new protocol of acoustic stimulation together with electrophysiological signal processing to track the steady state activity of ANFs. Mass potentials at the round window were recorded in response to repetitive 300-ms bursts of 1/3 octave band noise centered on a frequency probe. Analysis was assessed during the last 200-ms of the response to capture the steady-state response of ANFs. To eliminate the microphonic component reflecting the sensory cells activity, repetitive pairs of sounds of opposite polarities were used. The spectral analysis was calculated on the average of two consecutive responses, and the neural gain was calculated by dividing point-by-point the spectrum to sound over unstimulated condition. In response to low-sound-level stimulation, neural gain predominated in the low-frequency cochlear regions, while a second component of responses centered on higher cochlear frequency regions appeared beyond 30 dB SPL. At 60 dB SPL, neural gain showed a bimodal shape, with a notch near 5.6 kHz. In addition to correlate with the functional mapping of ANFs along the tonotopic axis, the deletion of low-SR fibers leads to a reduction in the high-frequency response, where the low-SR fibers are preferentially located. Thus, mass potentials at the round window may provide a useful tool to probe the SR-based distribution of ANFs in humans and in other species in which direct single-unit recordings are difficult to achieve or not feasible.

Tinnitus in Normal-Hearing Participants after Exposure to Intense Low-Frequency Sound and in Ménière's Disease Patients.

Tinnitus is one of the three classical symptoms of Ménière’s disease (MD), an inner ear disease that is often accompanied by endolymphatic hydrops. Previous studies indicate that tinnitus in MD patients is dominated by low frequencies, whereas tinnitus in non-hydropic pathologies is typically higher in frequency. Tinnitus of rather low-frequency (LF) quality was also reported to occur for about 90 s in normal-hearing participants after presentation of intense, LF sound (120 dB SPL, 30 Hz, 90 s). LF sound has been demonstrated to also cause temporary endolymphatic hydrops in animal models. Here, we quantify tinnitus in two study groups with chronic (MD patients) and presumably transient endolymphatic hydrops (normal-hearing participants after LF exposure) with a psychophysical procedure. Participants matched their tinnitus either with a pure tone of adjustable frequency and level or with a noise of adjustable spectral shape and level. Sensation levels of matching stimuli were lower for MD patients (mean: 8 dB SL) than for normal-hearing participants (mean: 15 dB SL). Transient tinnitus after LF-exposure occurred in all normal-hearing participants (N = 28). About half of the normal-hearing participants matched noise to their tinnitus, the other half chose a pure tone with frequencies below 2 kHz. MD patients matched their tinnitus with either high-frequency pure tones, mainly above 3 kHz, or with a noise. Despite a significant proportion of MD patients matching low-pass (roaring) noises to their tinnitus, the range of matched stimuli was more heterogeneous than previous data suggested. We propose that in those participants with noise-like tinnitus, the percept is probably generated by increased spontaneous activity of auditory nerve fibers with a broad range of characteristic frequencies, due to an impaired ion balance in the cochlea. For tonal tinnitus, additional mechanisms are conceivable: focal hair cell loss can result in decreased auditory nerve firing and a central auditory overcompensation. Also, normal-hearing participants after LF-exposure experience alterations in spontaneous otoacoustic emissions, which may contribute to a transient tonal tinnitus.

The potential use of low-frequency tones to locate regions of outer hair cell loss

Current methods used to diagnose cochlear hearing loss are limited in their ability to determine the location and extent of anatomical damage to various cochlear structures. In previous experiments, we have used the electrical potential recorded at the round window –the cochlear response (CR) –to predict the location of damage to outer hair cells in the gerbil. In a follow-up experiment, we applied 10 mM ouabain to the round window niche to reduce neural activity in order to quantify the neural contribution to the CR. We concluded that a significant proportion of the CR to a 762 Hz tone originated from phase-locking activity of basal auditory nerve fibers, which could have contaminated our conclusions regarding outer hair cell health. However, at such high concentrations, ouabain may have also affected the responses from outer hair cells, exaggerating the effect we attributed to the auditory nerve. In this study, we lowered the concentration of ouabain to 1 mM and determined the physiologic effects on outer hair cells using distortion-product otoacoustic emissions. As well as quantifying the effects of 1 mM ouabain on the auditory nerve and outer hair cells, we attempted to reduce the neural contribution to the CR by using near-infrasonic stimulus frequencies of 45 and 85 Hz, and hypothesized that these low-frequency stimuli would generate a cumulative amplitude function (CAF) that could reflect damage to hair cells in the apex more accurately than the 762 stimuli. One hour after application of 1 mM ouabain, CR amplitudes significantly increased, but remained unchanged in the presence of high-pass filtered noise conditions, suggesting that basal auditory nerve fibers have a limited contribution to the CR at such low frequencies.

Descending projections from the inferior colliculus to medial olivocochlear efferents: Mice with normal hearing, early onset hearing loss, and congenital deafness

Auditory efferent neurons reside in the brain and innervate the sensory hair cells of the cochlea to modulate incoming acoustic signals. Two groups of efferents have been described in mouse and this report will focus on the medial olivocochlear (MOC) system. Electrophysiological data suggest the MOC efferents function in selective listening by differentially attenuating auditory nerve fiber activity in quiet and noisy conditions. Because speech understanding in noise is impaired in age-related hearing loss, we asked whether pathologic changes in input to MOC neurons from higher centers could be involved. The present study investigated the anatomical nature of descending projections from the inferior colliculus (IC) to MOCs in 3-month old mice with normal hearing, and in 6-month old mice with normal hearing (CBA/CaH), early onset progressive hearing loss (DBA/2), and congenital deafness (homozygous Shaker-2). Anterograde tracers were injected into the IC and retrograde tracers into the cochlea. Electron microscopic analysis of double-labelled tissue confirmed direct synaptic contact from the IC onto MOCs in all cohorts. These labelled terminals are indicative of excitatory neurotransmission because they contain round synaptic vesicles, exhibit asymmetric membrane specializations, and are co-labelled with antibodies against VGlut2, a glutamate transporter. 3D reconstructions of the terminal fields indicate that in normal hearing mice, descending projections from the IC are arranged tonotopically with low frequencies projecting laterally and progressively higher frequencies projecting more medially. Along the mediolateral axis, the projections of DBA/2 mice with acquired high frequency hearing loss were shifted medially towards expected higher frequency projecting regions. Shaker-2 mice with congenital deafness had a much broader spatial projection, revealing abnormalities in the topography of connections. These data suggest that loss in precision of IC directed MOC activation could contribute to impaired signal detection in noise.

OPA1-related auditory neuropathy: site of lesion and outcome of cochlear implantation.

Hearing impairment is the second most prevalent clinical feature after optic atrophy in dominant optic atrophy associated with mutations in the OPA1 gene. In this study we characterized the hearing dysfunction in OPA1-linked disorders and provided effective rehabilitative options to improve speech perception. We studied two groups of OPA1 subjects, one comprising 11 patients (seven males; age range 13-79 years) carrying OPA1 mutations inducing haploinsufficiency, the other, 10 subjects (three males; age range 5-58 years) carrying OPA1 missense mutations. Both groups underwent audiometric assessment with pure tone and speech perception evaluation, and otoacoustic emissions and auditory brainstem response recording. Cochlear potentials were recorded through transtympanic electrocochleography from the group of patients harbouring OPA1 missense mutations and were compared to recordings obtained from 20 control subjects with normal hearing and from 19 subjects with cochlear hearing loss. Eight patients carrying OPA1 missense mutations underwent cochlear implantation. Speech perception measures and electrically-evoked auditory nerve and brainstem responses were obtained after 1 year of cochlear implant use. Nine of 11 patients carrying OPA1 mutations inducing haploinsufficiency had normal hearing function. In contrast, all but one subject harbouring OPA1 missense mutations displayed impaired speech perception, abnormal brainstem responses and presence of otoacoustic emissions consistent with auditory neuropathy. In electrocochleography recordings, cochlear microphonic had enhanced amplitudes while summating potential showed normal latency and peak amplitude consistent with preservation of both outer and inner hair cell activities. After cancelling the cochlear microphonic, the synchronized neural response seen in both normally-hearing controls and subjects with cochlear hearing loss was replaced by a prolonged, low-amplitude negative potential that decreased in both amplitude and duration during rapid stimulation consistent with neural generation. The use of cochlear implant improved speech perception in all but one patient. Brainstem potentials were recorded in response to electrical stimulation in five of six subjects, whereas no compound action potential was evoked from the auditory nerve through the cochlear implant. These findings indicate that underlying the hearing impairment in patients carrying OPA1 missense mutations is a disordered synchrony in auditory nerve fibre activity resulting from neural degeneration affecting the terminal dendrites. Cochlear implantation improves speech perception and synchronous activation of auditory pathways by bypassing the site of lesion.

Short-term synaptic depression is topographically distributed in the cochlear nucleus of the chicken.

In the auditory system, sounds are processed in parallel frequency-tuned circuits, beginning in the cochlea. Activity of auditory nerve fibers reflects this frequency-specific topographic pattern, known as tonotopy, and imparts frequency tuning onto their postsynaptic target neurons in the cochlear nucleus. In birds, cochlear nucleus magnocellularis (NM) neurons encode the temporal properties of acoustic stimuli by "locking" discharges to a particular phase of the input signal. Physiological specializations exist in gradients corresponding to the tonotopic axis in NM that reflect the characteristic frequency (CF) of their auditory nerve fiber inputs. One feature of NM neurons that has not been investigated across the tonotopic axis is short-term synaptic plasticity. NM offers a rather homogeneous population of neurons with a distinct topographical distribution of synaptic properties that is ideal for the investigation of specialized synaptic plasticity. Here we demonstrate for the first time that short-term synaptic depression (STD) is expressed topographically, where unitary high CF synapses are more robust with repeated stimulation. Correspondingly, high CF synapses drive spiking more reliably than their low CF counterparts. We show that postsynaptic AMPA receptor desensitization does not contribute to the observed difference in STD. Further, rate of recovery from depression, a presynaptic property, does not differ tonotopically. Rather, we show that another presynaptic feature, readily releasable pool (RRP) size, is tonotopically distributed and inversely correlated with vesicle release probability. Mathematical model results demonstrate that these properties of vesicle dynamics are sufficient to explain the observed tonotopic distribution of STD.

L-type CaV1.2 deletion in the cochlea but not in the brainstem reduces noise vulnerability: implication for CaV1.2-mediated control of cochlear BDNF expression

Voltage-gated L-type Ca2+ channels (L-VGCCs) like CaV1.2 are assumed to play a crucial role for controlling release of trophic peptides including brain-derived neurotrophic factor (BDNF). In the inner ear of the adult mouse, besides the well-described L-VGCC CaV1.3, CaV1.2 is also expressed. Due to lethality of constitutive CaV1.2 knock-out mice, the function of this ion channel as well as its putative relationship to BDNF in the auditory system is entirely elusive. We recently described that BDNF plays a differential role for inner hair cell (IHC) vesicles release in normal and traumatized condition. To elucidate a presumptive role of CaV1.2 during this process, two tissue-specific conditional mouse lines were generated. To distinguish the impact of CaV1.2 on the cochlea from that on feedback loops from higher auditory centers CaV1.2 was deleted, in one mouse line, under the Pax2 promoter (CaV1.2Pax2) leading to a deletion in the spiral ganglion neurons, dorsal cochlear nucleus, and inferior colliculus. In the second mouse line, the Egr2 promoter was used for deleting CaV1.2 (CaV1.2Egr2) in auditory brainstem nuclei. In both mouse lines, normal hearing threshold and equal number of IHC release sites were observed. We found a slight reduction of auditory brainstem response wave I amplitudes in the CaV1.2Pax2 mice, but not in the CaV1.2Egr2 mice. After noise exposure, CaV1.2Pax2 mice had less-pronounced hearing loss that correlated with maintenance of ribbons in IHCs and less reduced activity in auditory nerve fibers, as well as in higher brain centers at supra-threshold sound stimulation. As reduced cochlear BDNF mRNA levels were found in CaV1.2Pax2 mice, we suggest that a CaV1.2-dependent step may participate in triggering part of the beneficial and deteriorating effects of cochlear BDNF in intact systems and during noise exposure through a pathway that is independent of CaV1.2 function in efferent circuits.

How Broadband Speech May Avoid Neural Firing Rate Saturation at High Intensities and Maintain Intelligibility.

While broadband speech may remain perfectly intelligible at levels exceeding 90 dB, narrowband speech intelligibility (e.g., 2/3-octave passband centered at 1.5 kHz) may decline by 25% or more at moderate intensities (e.g., 75 dB). This "rollover" effect is substantially reduced, however, when a speech band is accompanied by flanking bands of white noise [J.A. Bashford, R.M. Warren, & P.W. Lenz, 2005, J. Acoust. Soc. Am. 117, 365-369 (2005)], suggesting that lateral suppression helps preserve broadband speech intelligibility at high levels. The present study found that when noise flankers were presented individually at a low spectrum level (-30 dB relative to the speech) only the higher-frequency flanker produced a significant intelligibility increase. However, the lower-frequency flanking noise did produce an equivalent increase when its spectrum level was raised 10 dB. This asymmetrical intensity requirement for noise flankers links the effective dynamic range of speech intelligibility to reported characteristics of both lateral (two-tone) suppression of auditory nerve (AN) fiber activity and lateral inhibition of secondary cells of the cochlear nucleus. These and other observations will be discussed in the broader context of how various auditory mechanisms help preserve speech intelligibility at high intensities by reducing firing rate saturation. [Supported by NIH.].

A Clinical Study of Cortical Auditory Evoked Potentials in Cochlear Implantees

Normal maturation of central auditory pathways is a precondition for the optimal development of speech and language skills in children. The temporal cortex gets acoustically tagged due to auditory stimulation and important changes occur in the higher auditory centers due to hearing loss of any type and degree. Cochlear implantation increases auditory sensitivity by direct electrical activation of auditory nerve fibers, enabling phonemic awareness, discrimination and identification ultimately yielding speech understanding. Early implantation stimulates a brain that has not been re-organized and will therefore be more receptive to auditory input and greater auditory capacity. Cortical potentials have enabled us to objectively study this phenomenon. To assess the outcomes of Cochlear implants on the auditory cortex by analyzing cortical auditory evoked potentials (CAEPs) in the habilitation period. This prospective clinical study was performed in 30 pre-lingual candidates with varied etiology of deafness who underwent cochlear implantation at our institute over the last 1year. The study group had two cohorts (group-1: 0-8years and group-2: 8-15years) which included candidates with normal inner ear and no syndromes or handicaps. All implantees in the study group underwent CAEP testing at 6months and 1year post-implantation and comparison of the CAEP wave parameters (P1 amplitude, P1 latency and P1 morphology) were done between the two cohorts. In children Implanted early (group-1) there was an early onset rapid increase in P1 amplitude along with a decrease in P1 latency during the follow-up period. Significant change in the CAEP wave morphology was also notable in group-1 unlike in group-2. Candidates who experienced less than 3years of auditory deprivation before implantation showed P1 latencies, which fell into the range of normal children within 6months of habilitation. Children with more than 6years of auditory deprivation, however, generally did not develop normal P1 latencies or morphology even after 1year of habilitation. The overall outcome with CAEP was much better in group-1 as compared to group-2 and the observations were is in comparison with the existing world literature. The advent of CAEP has objectively proved beyond doubt that there is a critical age for stimulating the auditory brain via cochlear implantation. There is considerable evidence for a developmental sensitive period, during which the auditory cortex is highly plastic. If sensory input is deprived to the auditory system during this sensitive period, then the central auditory system is susceptible to large scale reorganization. Restoring input to the auditory system by Cochlear Implant at an early age can provide the stimulation necessary to preserve the auditory pathways. However, if auditory input is not restored until after this developmental period, then the cross-modal reorganized pathways may exhibits abnormal functional characteristics as observed in recorded P1 amplitude, latencies and morphologies of CAEPs.

Postnatal development of the endbulb of Held in congenitally deaf cats

The endbulbs of Held are formed by the ascending branches of myelinated auditory nerve fibers and represent one of the largest synaptic endings in the brain. Normally, these endings are highly branched and each can form up to 1000 dome-shaped synapses. The deaf white cat is a model of congenital deafness involving a type of cochleosaccular degeneration that mimics the Scheibe deformity in humans. Endbulbs of mature deaf white cats exhibit reduced branching, hypertrophy of postsynaptic densities (PSDs), and changes in synaptic vesicle density. Because cats are essentially deaf at birth, we sought to determine if the progression of brain abnormalities was linked in time to the failure of normal hearing development. The rationale was that the lack of sound-evoked activity would trigger pathologic change in deaf kittens. The cochleae of deaf cats did not exhibit abnormal morphology at birth. After the first postnatal week, however, the presence of a collapsed scala media signaled the difference between deaf and hearing cats. By working backwards in age, endbulbs of deaf cats expressed flattened and elongated PSDs and increased synaptic vesicle density as compared to normal endbulbs. These differences are present at birth in some white kittens, presaging deafness despite their normal cochlear histology. We speculate that hearing pathology is signaled by a perinatal loss of spontaneous bursting activity in auditory nerve fibers or perhaps by some factor released by hair cell synapses before obliteration of the organ of Corti.

Spontaneous Activity of Auditory Nerve Fibers in the Barn Owl (Tyto alba): Analyses of Interspike Interval Distributions

In vertebrate auditory systems, the conversion from graded receptor potentials across the hair-cell membrane into stochastic spike trains of the auditory nerve (AN) fibers is performed by ribbon synapses. The statistics underlying this process constrain auditory coding but are not precisely known. Here, we examine the distributions of interspike intervals (ISIs) from spontaneous activity of AN fibers of the barn owl (Tyto alba), a nocturnal avian predator whose auditory system is specialized for precise temporal coding. The spontaneous activity of AN fibers, with the exception of those showing preferred intervals, is commonly thought to result from excitatory events generated by a homogeneous Poisson point process, which lead to spikes unless the fiber is refractory. We show that the ISI distributions in the owl are better explained as resulting from the action of a brief refractory period ( approximately 0.5 ms) on excitatory events generated by a homogeneous stochastic process where the distribution of interevent intervals is a mixture of an exponential and a gamma distribution with shape factor 2, both with the same scaling parameter. The same model was previously shown to apply to AN fibers in the cat. However, the mean proportions of exponentially versus gamma-distributed intervals in the mixture were different for cat and owl. Furthermore, those proportions were constant across fibers in the cat, whereas they covaried with mean spontaneous rate and with characteristic frequency in the owl. We hypothesize that in birds, unlike in mammals, more than one ribbon may provide excitation to most fibers, accounting for the different proportions, and that variation in the number of ribbons may underlie the variation in the proportions.