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Local and privileged expression of dendritic proteins allows segregation of distinct functions in a single neuron but may represent one of the underlying mechanisms for early and insidious presentation of sensory neuropathy. Tangible characteristics of early hearing loss (HL) are defined in correlation with nascent hidden hearing loss (HHL) in humans and animal models. Despite the plethora of causes of HL, only two prevailing mechanisms for HHL have been identified, and in both cases, common structural deficits are implicated in inner hair cell synapses, and demyelination of the auditory nerve (AN). We uncovered that Na+-activated K+ (KNa) mRNA and channel proteins are distinctly and locally expressed in dendritic projections of primary ANs and genetic deletion of KNa channels (Kcnt1 and Kcnt2) results in the loss of proper AN synaptic function, characterized as HHL, without structural synaptic alterations. We further demonstrate that the local functional synaptic alterations transition from HHL to increased hearing-threshold, which entails changes in global Ca2+ homeostasis, activation of caspases 3/9, impaired regulation of inositol triphosphate receptor 1 (IP3R1), and apoptosis-mediated neurodegeneration. Thus, the present study demonstrates how local synaptic dysfunction results in an apparent latent pathological phenotype (HHL) and, if undetected, can lead to overt HL. It also highlights, for the first time, that HHL can precede structural synaptic dysfunction and AN demyelination. The stepwise cellular mechanisms from HHL to canonical HL are revealed, providing a platform for intervention to prevent lasting and irreversible age-related hearing loss (ARHL).

Noninvasive transcranial electric stimulation is increasingly being used as an advantageous therapy alternative that may activate deep tissues while avoiding drug side-effects. However, not only is there limited evidence for activation of deep tissues by transcranial electric stimulation, its evoked human sensation is understudied and often dismissed as a placebo or secondary effect. By systematically characterizing the human sensation evoked by transcranial alternating-current stimulation, we observed not only stimulus frequency and electrode position dependencies specific for auditory and visual sensation but also a broader presence of somatic sensation ranging from touch and vibration to pain and pressure. We found generally monotonic input-output functions at suprathreshold levels, and often multiple types of sensation occurring simultaneously in response to the same electric stimulation. We further used a recording circuit embedded in a cochlear implant to directly and objectively measure the amount of transcranial electric stimulation reaching the auditory nerve, a deep intercranial target located in the densest bone of the skull. We found an optimal configuration using an ear canal electrode and low-frequency (

Electrical stimulation of the auditory nerve with a penetrating intraneural (IN) electrode in acutely deafened cats produces much more restricted spread of excitation than is obtained in that preparation with a conventional cochlear implant (CI) as reported by Middlebrooks and Snyder (J Assoc Res Otolaryngol 8:258-279, 2007). That suggests that a future auditory prosthesis employing IN stimulation might offer human patients greater frequency selectivity than is available with a present-day CI. Nevertheless, it is a concern that the electrical field produced by an IN electrode might be too restricted to produce adequate stimulation of the partially depopulated auditory nerve of a deaf patient. We evaluated this by testing responses to IN and CI stimulation in adult-deafened cats. Activation of the auditory pathway was monitored by recording from the central nucleus of the inferior colliculus (ICC). Cats deaf for 153-277 days exhibited a ~ 30 % loss of auditory nerve fibers compared to cats deaf for

Sensorineural hearing impairment is the most common form of hearing loss, and encompasses pathologies of the cochlea and the auditory nerve. Hearing impairment caused by abnormal neural encoding of sound stimuli despite preservation of sensory transduction and amplification by outer hair cells is known as 'auditory neuropathy'. This term was originally coined for a specific type of hearing impairment affecting speech comprehension beyond changes in audibility: patients with this condition report that they "can hear but cannot understand". This type of hearing impairment can be caused by damage to the sensory inner hair cells (IHCs), IHC ribbon synapses or spiral ganglion neurons. Human genetic and physiological studies, as well as research on animal models, have recently shown that disrupted IHC ribbon synapse function--resulting from genetic alterations that affect presynaptic glutamate loading of synaptic vesicles, Ca(2+) influx, or synaptic vesicle exocytosis--leads to hearing impairment termed 'auditory synaptopathy'. Moreover, animal studies have demonstrated that sound overexposure causes excitotoxic loss of IHC ribbon synapses. This mechanism probably contributes to hearing disorders caused by noise exposure or age-related hearing loss. This Review provides an update on recently elucidated sensory, synaptic and neural mechanisms of hearing impairment, their corresponding clinical findings, and discusses current rehabilitation strategies as well as future therapies.

Mutations in the OTOF gene encoding otoferlin result in a disrupted function of the ribbon synapses with impairment of the multivesicular glutamate release. Most affected subjects present with congenital hearing loss and abnormal auditory brainstem potentials associated with preserved cochlear hair cell activities (otoacoustic emissions, cochlear microphonics [CMs]). Transtympanic electrocochleography (ECochG) has recently been proposed for defining the details of potentials arising in both the cochlea and auditory nerve in this disorder, and with a view to shedding light on the pathophysiological mechanisms underlying auditory dysfunction. We review the audiological and electrophysiological findings in children with congenital profound deafness carrying two mutant alleles of the OTOF gene. We show that cochlear microphonic (CM) amplitude and summating potential (SP) amplitude and latency are normal, consistently with a preserved outer and inner hair cell function. In the majority of OTOF children, the SP component is followed by a markedly prolonged low-amplitude negative potential replacing the compound action potential (CAP) recorded in normally-hearing children. This potential is identified at intensities as low as 90 dB below the behavioral threshold. In some ears, a synchronized CAP is superimposed on the prolonged responses at high intensity. Stimulation at high rates reduces the amplitude and duration of the prolonged potentials, consistently with their neural generation. In some children, however, the ECochG response only consists of the SP, with no prolonged potential. Cochlear implants restore hearing sensitivity, speech perception and neural CAP by electrically stimulating the auditory nerve fibers. These findings indicate that an impaired multivesicular glutamate release in OTOF-related disorders leads to abnormal auditory nerve fiber activation and a consequent impairment of spike generation. The magnitude of these effects seems to vary, ranging from no auditory nerve fiber activation to an abnormal generation of EPSPs that occasionally trigger a synchronized electrical activity, resulting in high-threshold CAPs.

PURPOSE OF REVIEW: Electric stimulation is a potent means of neuromodulation that has been used to restore hearing and minimize tremor, but its application on tinnitus symptoms has been limited. We examine recent evidence to identify the knowledge gaps in the use of electric stimulation for tinnitus treatment. RECENT FINDINGS: Recent studies using electric stimulation to suppress tinnitus in humans are categorized according to their points of attacks. First, noninvasive, direct current stimulation uses an active electrode in the ear canal, tympanic membrane, or temporal scalp. Second, inner ear stimulation uses charge-balanced biphasic stimulation by placing an active electrode on the promontory or round window, or a cochlear implant array in the cochlea. Third, intraneural implants can provide targeted stimulation of specific sites along the auditory pathway. Although these studies demonstrated some success in tinnitus suppression, none established a link between tinnitus suppression efficacy and tinnitus-generating mechanisms. SUMMARY: Electric stimulation provides a unique opportunity to suppress tinnitus. Challenges include matching electric stimulation sites and patterns to tinnitus locus and type, meeting the oftentimes-contradictory demands between tinnitus suppression and other indications, such as speech understanding, and justifying the costs and risks of electric stimulation for tinnitus symptoms.

Abnormal auditory adaptation is a standard clinical tool for diagnosing auditory nerve disorders due to acoustic neuromas. In the present study we investigated auditory adaptation in auditory neuropathy owing to disordered function of inner hair cell ribbon synapses (temperature-sensitive auditory neuropathy) or auditory nerve fibres. Subjects were tested when afebrile for (i) psychophysical loudness adaptation to comfortably-loud sustained tones; and (ii) physiological adaptation of auditory brainstem responses to clicks as a function of their position in brief 20-click stimulus trains (#1, 2, 3 … 20). Results were compared with normal hearing listeners and other forms of hearing impairment. Subjects with ribbon synapse disorder had abnormally increased magnitude of loudness adaptation to both low (250 Hz) and high (8000 Hz) frequency tones. Subjects with auditory nerve disorders had normal loudness adaptation to low frequency tones; all but one had abnormal adaptation to high frequency tones. Adaptation was both more rapid and of greater magnitude in ribbon synapse than in auditory nerve disorders. Auditory brainstem response measures of adaptation in ribbon synapse disorder showed Wave V to the first click in the train to be abnormal both in latency and amplitude, and these abnormalities increased in magnitude or Wave V was absent to subsequent clicks. In contrast, auditory brainstem responses in four of the five subjects with neural disorders were absent to every click in the train. The fifth subject had normal latency and abnormally reduced amplitude of Wave V to the first click and abnormal or absent responses to subsequent clicks. Thus, dysfunction of both synaptic transmission and auditory neural function can be associated with abnormal loudness adaptation and the magnitude of the adaptation is significantly greater with ribbon synapse than neural disorders.

Objectives/hypothesisTo evaluate a transcanal approach for placement of a stimulating electrode array in the cochlear nerve.Study designProspective cadaveric temporal bone study.MethodsTen human cadaveric temporal bones were dissected. Both a facial recess approach with mastoidectomy and a transcanal approach using the novel technique were performed in each bone. A middle fossa dissection of the internal auditory canal was performed to confirm the position of the electrode in the cochlear nerve.ResultsThe transcanal approach offered a direct approach to the cochlear nerve in all 10 bones. The procedure was quicker than the facial recess approach and did not endanger the facial or chorda tympani nerves. Inspection of the medial end of the internal auditory canal confirmed correct placement of the electrode in the cochlear nerve. In contrast, anatomical constraints, specifically the position of the facial nerve, blocked access to the cochlear nerve by the facial recess approach in three of the specimens to achieve the exposure to place the electrode at a perpendicular angle to the cochlear nerve. Sacrifice of the chorda tympani was necessary in five of the seven bones in which the cochlear nerve could be accessed.ConclusionsThe transcanal approach offers a simpler, safer approach for cochlear nerve implantation compared to the facial recess approach. This approach can be accomplished in less time and avoids the hazards of dissection around the facial nerve. Use of the proposed approach will facilitate development of intraneural stimulation for an improved auditory prosthesis.

ObjectivesAuditory cortical N100s were examined in ten auditory neuropathy (AN) subjects as objective measures of impaired hearing.MethodsLatencies and amplitudes of N100 in AN to increases of frequency (4-50%) or intensity (4-8 dB) of low (250 Hz) or high (4000 Hz) frequency tones were compared with results from normal-hearing controls. The sites of auditory nerve dysfunction were pre-synaptic (n=3) due to otoferlin mutations causing temperature sensitive deafness, post-synaptic (n=4) affecting other cranial and/or peripheral neuropathies, and undefined (n=3).ResultsAN consistently had N100s only to the largest changes of frequency or intensity whereas controls consistently had N100s to all but the smallest frequency and intensity changes. N100 latency in AN was significantly delayed compared to controls, more so for 250 than for 4000 Hz and more so for changes of intensity compared to frequency. N100 amplitudes to frequency change were significantly reduced in ANs compared to controls, except for pre-synaptic AN in whom amplitudes were greater than controls. N100 latency to frequency change of 250 but not of 4000 Hz was significantly related to speech perception scores.ConclusionsAs a group, AN subjects' N100 potentials were abnormally delayed and smaller, particularly for low frequency. The extent of these abnormalities differed between pre- and post-synaptic forms of the disorder.SignificanceAbnormalities of auditory cortical N100 in AN reflect disorders of both temporal processing (low frequency) and neural adaptation (high frequency). Auditory N100 latency to the low frequency provides an objective measure of the degree of impaired speech perception in AN.

Otoferlin is involved in neurotransmitter release at the synapse between inner hair cells (IHCs) and auditory nerve fibres, and mutations in the OTOF gene result in severe to profound hearing loss. Abnormal sound-evoked cochlear potentials were recorded with transtympanic electrocochleography from four children with otoferlin (OTOF) mutations to evaluate physiological effects in humans of abnormal neurotransmitter release from IHCs. The subjects were profoundly deaf with absent auditory brainstem responses and preserved otoacoustic emissions consistent with auditory neuropathy. Two children were compound heterozygotes for mutations c.2732_2735dupAGCT and p.Ala964Glu; one subject was homozygous for mutation p.Phe1795Cys, and one was compound heterozygote for two novel mutations c.1609delG in exon 16 and c.1966delC in exon 18. Cochlear potentials evoked by clicks from 60 to 120 dB peak equivalent sound pressure level were compared to recordings obtained from 16 normally hearing children. Cochlear microphonic (CM) was recorded with normal amplitudes from all but one ear. After cancelling CM, cochlear potentials were of negative polarity with reduced amplitude and prolonged duration compared to controls. These cochlear potentials were recorded as low as 50-90 dB below behavioural thresholds in contrast to the close correlation in controls between cochlear potentials and behavioural threshold. Summating potential was identified in five out of eight ears with normal latency whilst auditory nerve compound action potentials were either absent or of low amplitude. Stimulation at high rates reduced amplitude and duration of the prolonged potentials, consistent with neural generation. This study suggests that mechano-electrical transduction and cochlear amplification are normal in patients with OTOF mutations. The low-amplitude prolonged negative potentials are consistent with decreased neurotransmitter release resulting in abnormal dendritic activation and impairment of auditory nerve firing.

Autosomal dominant optic atrophy (DOA) is a retinal neuronal degenerative disease characterized by a progressive bilateral visual loss. We report on two affected members of a family with dominantly inherited neuropathy of both optic and auditory nerves expressed by impaired visual acuity, moderate pure tone hearing loss, and marked loss of speech perception. We investigated cochlear abnormalities accompanying the hearing loss and the effects of cochlear implantation. We sequenced OPA1 gene and recorded cochlear receptor and neural potentials before cochlear implantation. Genetic analysis identified R445H mutation in OPA1 gene. Audiological studies showed preserved cochlear receptor outer hair cell activities (otoacoustic emissions) and absent or abnormally delayed auditory brainstem responses (ABRs). Trans-tympanic electrocochleography (ECochG) showed prolonged low amplitude negative potentials without auditory nerve compound action potentials. The latency of onset of the cochlear potentials was within the normal range found for inner hair cell summating receptor potentials. The duration of the negative potential was reduced to normal during rapid stimulation consistent with adaptation of neural sources generating prolonged cochlear potentials. Both subjects had cochlear implants placed with restoration of hearing thresholds, speech perception, and synchronous activity in auditory brainstem pathways. The results suggest that deafness accompanying this OPA1 mutation is due to altered function of terminal unmyelinated portions of auditory nerve. Electrical stimulation of the cochlea activated proximal myelinated portions of auditory nerve to restore hearing.

ObjectiveAuditory temporal processes in quiet are impaired in auditory neuropathy (AN) similar to normal hearing subjects tested in noise. N100 latencies were measured from AN subjects at several tone intensities in quiet and noise for comparison with a group of normal hearing individuals.MethodsSubjects were tested with brief 100 ms tones (1.0 kHz, 100-40 dB SPL) in quiet and in continuous noise (90 dB SPL). N100 latency and amplitude were analyzed as a function of signal intensity and audibility.ResultsN100 latency in AN in quiet was delayed and amplitude was reduced compared to the normal group; the extent of latency delay was related to psychoacoustic measures of gap detection threshold and speech recognition scores, but not to audibility. Noise in normal hearing subjects was accompanied by N100 latency delays and amplitude reductions paralleling those found in AN tested in quiet. Additional N100 latency delays and amplitude reductions occurred in AN with noise.ConclusionsN100 latency to tones and performance on auditory temporal tasks were related in AN subjects. Noise masking in normal hearing subjects affected N100 latency to resemble AN in quiet.SignificanceN100 latency to tones may serve as an objective measure of the efficiency of auditory temporal processes.

ObjectiveTranstympanic electrocochleography (ECochG) was recorded bilaterally in children and adults with auditory neuropathy (AN) to evaluate receptor and neural generators.MethodsTest stimuli were clicks from 60 to 120dB p.e. SPL. Measures obtained from eight AN subjects were compared to 16 normally hearing children.ResultsReceptor cochlear microphonics (CMs) in AN were of normal or enhanced amplitude. Neural compound action potentials (CAPs) and receptor summating potentials (SPs) were identified in five AN ears. ECochG potentials in those ears without CAPs were of negative polarity and of normal or prolonged duration. We used adaptation to rapid stimulus rates to distinguish whether the generators of the negative potentials were of neural or receptor origin. Adaptation in controls resulted in amplitude reduction of CAP twice that of SP without affecting the duration of ECochG potentials. In seven AN ears without CAP and with prolonged negative potential, adaptation was accompanied by reduction of both amplitude and duration of the negative potential to control values consistent with neural generation. In four ears without CAP and with normal duration potentials, adaptation was without effect consistent with receptor generation. In five AN ears with CAP, there was reduction in amplitude of CAP and SP as controls but with a significant decrease in response duration.ConclusionsThree patterns of cochlear potentials were identified in AN: (1) presence of receptor SP without CAP consistent with pre-synaptic disorder of inner hair cells; (2) presence of both SP and CAP consistent with post-synaptic disorder of proximal auditory nerve; (3) presence of prolonged neural potentials without a CAP consistent with post-synaptic disorder of nerve terminals.SignificanceCochlear potential measures may identify pre- and post-synaptic disorders of inner hair cells and auditory nerves in AN.

The clawed frog Xenopus laevis produces vocalizations consisting of distinct patterns of clicks. This study provides the first description of spontaneous, pure-tone and communication-signal evoked discharge properties of auditory nerve (n.VIII) fibers and dorsal medullary nucleus (DMN) cells in an obligatorily aquatic anuran. Responses of 297 n.VIII and 253 DMN units are analyzed for spontaneous rates (SR), frequency tuning, rate-intensity functions, and firing rate adaptation, with a view to how these basic characteristics shape responses to recorded call stimuli. Response properties generally resemble those in partially terrestrial anurans. Broad tuning exists across characteristic frequencies (CFs). Threshold minima are -101 dB re 1 mm/s at 675 Hz; -87 dB at 1,600 Hz; and -61 dB at 3,000 Hz (-90, -77, and -44 dB re 1 Pa, respectively), paralleling the peak frequency of vocalizations at 1.2-1.6 kHz with approximately 500 Hz in 3 dB bandwidth. SRs range from 0 to 80 (n.VIII) and 0 to 73 spikes/s (DMN). Nerve and DMN units of all CFs follow click rates in natural calls, < or =67 clicks/s and faster. Units encode clicks with a single spike, double spikes, or bursts. Spike times correlate closely with click envelopes. No temporal filtering for communicative click rates occurs in either n.VIII or the DMN.

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.

ObjectiveTo define the incidence of measurable vestibular disorders in patients with auditory and peripheral neuropathies.DesignDescriptive study of the case features of auditory neuropathy in 14 patients, 8 of whom had concomitant peripheral neuropathies.SettingUniversity referral center.PatientsFourteen patients aged from 10 to 75 years and diagnosed as having auditory neuropathy, 8 of whom had concomitant peripheral neuropathies.Main outcome measuresIncidence of abnormal vestibular caloric test results and the relationship of such incidence to clinical variables including the ages of the subjects, the presence of a concomitant peripheral neuropathy, vestibular symptoms, and audiological findings.ResultsAbnormal vestibular caloric test results occurred in 9 of the 14 patients. These 9 patients were on average older (35.6 years) than patients with normal caloric responses (17.8 years). Seven of the 9 patients with abnormal caloric responses had concomitant peripheral neuropathies compared with only 1 of the 5 patients with normal caloric responses. None of the 14 patients experienced symptoms of vestibular disorder.ConclusionsAsymptomatic vestibular disorders are common in patients with auditory neuropathy when a peripheral neuropathy is also present. The reason for the abnormal vestibular test results is likely a neuropathy of the vestibular nerves. Arch Otolaryngol Head Neck Surg. 2000;126:1453-1456

ObjectiveThe objective of this experiment was to address: 1) whether normal efferent system function is required for normal cochlear tuning as measured by distortion product otoacoustic emission (DPOAE) suppression in humans and 2) whether cochlear function, assessed by DPOAE suppression tuning, is normal in a small group of patients with auditory neuropathy.DesignDPOAE suppression tuning curves (STCs) are similar to other physiologic measures of tuning. They are generated by evoking a DPOAE with two simultaneously presented pure tones and then suppressing the distortion product with a third tone of varying frequency and level. In this study, DPOAE STCs were generated with f2 frequencies of 1500, 3000, and 6000 Hz in 15 normal-hearing adults and four subjects with documented auditory neuropathy. Tuning curve width, slope and tip characteristics, as well as rate of suppression growth were measured in each group. Contralateral suppression of otoacoustic emissions (OAEs) was also recorded as an index of medial efferent function.ResultsResults show that the four subjects with auditory neuropathy lacked efferent suppression of OAEs. However, these four subjects showed normal estimates of cochlear tuning as measured by DPOAE suppression results.ConclusionsThis finding suggests that normal efferent system function is not required at the time of test for normal DPOAE suppression tuning. It also suggests that cochlear function as evaluated by detailed measures of DPOAE suppression, is normal in these "typical" patients with auditory neuropathy.

UNLABELLED: The aim of this work was to assess the hearing impairment in patients with hereditary motor and sensory neuropathy (HMSN). Elevation of pure tone thresholds in the presence of preserved inner ear function as suggested by cochlear microphonics (CM), absent or markedly abnormal brainstem auditory evoked potentials (BAEP), and elevation of speech perception out of proportion to the pure tone loss were found in the patients. From 28 members of a Gypsy family, we examined two siblings aged 31 and 30 years and their nephew aged 20 years, all suffering from HMSN that was associated with auditory neuropathy. All three affected members with difficulty of understanding speech had following investigations: pure tone and speech audiograms, BAEP, cochlear microphonics, and nerve conduction studies (NCV). RESULTS: the older two siblings had a flat 80 dB audiogram, whereas the younger one has flat 20 dB audiogram on the Lt. ear and 30 dB audiogram on the Rt. ear. All had no speech comprehension and no BAEP. Two patients had preserved cochlear microphonics on one ear. Peripheral nerves were electrically not elicitable, however, at the beginning of the disease nerve conduction was slow. CONCLUSION: in all three affected members with distinct clinical picture of HMSN their hearing impairment was proved to be due to severe auditory neuropathy in the presence of preserved inner ear function.

UNLABELLED: The aim of this work was to assess the hearing impairment in patients with hereditary motor and sensory neuropathy (HMSN). Elevation of pure tone thresholds in the presence of preserved inner ear function as suggested by cochlear microphonics (CM), absent or markedly abnormal brainstem auditory evoked potentials (BAEP), and elevation of speech perception out of proportion to the pure tone loss were found in the patients. From 28 members of a Gypsy family, we examined two siblings aged 31 and 30 years and their nephew aged 20 years, all suffering from HMSN that was associated with auditory neuropathy. All three affected members with difficulty of understanding speech had following investigations: pure tone and speech audiograms, BAEP, cochlear microphonics, and nerve conduction studies (NCV). RESULTS: the older two siblings had a flat 80 dB audiogram, whereas the younger one has flat 20 dB audiogram on the Lt. ear and 30 dB audiogram on the Rt. ear. All had no speech comprehension and no BAEP. Two patients had preserved cochlear microphonics on one ear. Peripheral nerves were electrically not elicitable, however, at the beginning of the disease nerve conduction was slow. CONCLUSION: in all three affected members with distinct clinical picture of HMSN their hearing impairment was proved to be due to severe auditory neuropathy in the presence of preserved inner ear function.

Auditory neuropathy affects the normal synchronous activity in the auditory nerve, without affecting the amplification function in the inner ear. Patients with auditory neuropathy often complain that they can hear sounds, but cannot understand speech. Here we report psychophysical tests indicating that these patients' poor speech recognition is due to a severe impairment in their temporal processing abilities. We also simulate this temporal processing impairment in normally hearing listeners and produce similar speech recognition deficits. This study demonstrates the importance of neural synchrony for auditory perceptions including speech recognition in humans. The results should contribute to better diagnosis and treatment of auditory neuropathy.

Ten patients presented as children or young adults with hearing impairments that, by behavioural and physiological testing, were compatible with a disorder of the auditory portion of the VIII cranial nerve. Evidence of normal cochlear outer hair cell function was provided by preservation of otoacoustic emissions and cochlear microphonics in all of the patients. Auditory brainstem potentials showed evidence of abnormal auditory pathway function beginning with the VIII nerve: the potentials were absent in nine patients and severely distorted in one patient. Auditory brainstem reflexes (middle ear muscles; crossed suppression of otoacoustic emissions) were absent in all of the tested patients. Behavioural audiometric testing showed a mild to moderate elevation of pure tone threshold in nine patients. The extent of the hearing loss, if due to cochlear receptor damage, should not have resulted in the loss of auditory brainstem potentials. The shape of the pure tone loss varied, being predominantly low frequency in five patients, flat across all frequencies in three patients and predominantly high frequency in two patients. Speech intelligibility was tested in eight patients, and in six was affected out of proportion to what would have been expected if the pure tone loss were of cochlear origin. The patients were otherwise neurologically normal when the hearing impairment was first manifest. Subsequently, eight of these patients developed evidence for a peripheral neuropathy. The neuropathy was hereditary in three and sporadic in five. We suggest that this type of hearing impairment is due to a disorder of auditory nerve function and may have, as one of its causes, a neuropathy of the auditory nerve, occurring either in isolation or as part of a generalized neuropathic process.

Auditory brain-stem potentials (ABRs) were studied in cats for up to 6 weeks after kainic acid had been injected unilaterally into the cochlear nucleus (CN) producing extensive neuronal destruction. The ABR components were labeled by the polarity at the vertex (P, for positive) and their order of appearance (the arabic numerals 1, 2, etc.). Component P1 can be further subdivided into 2 subcomponents, P1a and P1b. The assumed correspondence between the ABR components in cat and man is indicated by providing human Roman numeral designations in parentheses following the feline notation, e.g., P2 (III). To stimulation of the ear ipsilateral to the injection, the ABR changes consisted of a loss of components P2 (III) and P3 (IV), and an attenuation and prolongation of latency of components P4 (V) and P5 (VI). The sustained potential shift from which the components arose was not affected. Wave P1a (I) was also slightly but significantly attenuated compatible with changes of excitability of nerve VIII in the cochlea secondary to cochlear nucleus destruction. Unexpectedly, to stimulation of the ear contralateral to the injection side, waves P2 (III), P3 (IV), and P4 (V) were also attenuated and delayed in latency but to a lesser degree than to stimulation of the ear ipsilateral to the injection. Changes in binaural interaction of the ABR following cochlear nucleus lesions were similar to those produced in normal animals by introducing a temporal delay of the input to one ear. The results of the present set of studies using kainic acid to induce neuronal loss in auditory pathway when combined with prior lesion and recording experiments suggest that each of the components of the ABR requires the integrity of an anatomically diffuse system comprising a set of neurons, their axons, and the neurons on which they terminate. Disruption of any portion of the system will alter the amplitude and/or the latency of that component.

Auditory brain-stem potentials (ABRs) were studied in cats for up to 6 weeks after kainic acid had been injected unilaterally into the cochlear nucleus (CN) producing extensive neuronal destruction. The ABR components were labeled by the polarity at the vertex (P, for positive) and their order of appearance (the arabic numerals 1, 2, etc.). Component P1 can be further subdivided into 2 subcomponents, P1a and P1b. The assumed correspondence between the ABR components in cat and man is indicated by providing human Roman numeral designations in parentheses following the feline notation, e.g., P2 (III). To stimulation of the ear ipsilateral to the injection, the ABR changes consisted of a loss of components P2 (III) and P3 (IV), and an attenuation and prolongation of latency of components P4 (V) and P5 (VI). The sustained potential shift from which the components arose was not affected. Wave P1a (I) was also slightly but significantly attenuated compatible with changes of excitability of nerve VIII in the cochlea secondary to cochlear nucleus destruction. Unexpectedly, to stimulation of the ear contralateral to the injection side, waves P2 (III), P3 (IV), and P4 (V) were also attenuated and delayed in latency but to a lesser degree than to stimulation of the ear ipsilateral to the injection. Changes in binaural interaction of the ABR following cochlear nucleus lesions were similar to those produced in normal animals by introducing a temporal delay of the input to one ear. The results of the present set of studies using kainic acid to induce neuronal loss in auditory pathway when combined with prior lesion and recording experiments suggest that each of the components of the ABR requires the integrity of an anatomically diffuse system comprising a set of neurons, their axons, and the neurons on which they terminate. Disruption of any portion of the system will alter the amplitude and/or the latency of that component.

Discrete lesions of the brain stem auditory pathway in cats were found to have complex effects on the auditory brain stem response (ABR). These effects ranged from an amplitude change on only a single component of the ABR to latency and amplitude changes for that component plus some or all of the subsequent components. Lesions of certain portions of the classical primary auditory pathway (i.e., the dorsal cochlear nucleus, the dorsal acoustic stria, the lateral superior olivary nucleus, the posterior portion of the lateral lemniscus and the inferior colliculus) were not associated with changes in the ABR prior to component P5. Except for midline lesions, the effects of a brain stem lesion on the ABR were quite different for ipsilateral and contralateral stimulation. The predominant effect of brain stem lesions on the ABR was an attenuation of the amplitudes of the components and only an occasional increase in their latency. Opposite effects, i.e., increases in amplitude or decreases in latency, were rare. The acute effects of brain stem lesions on the ABR could be transient and not persist in chronic recordings. The components of the ABR were primarily affected by the following lesions. Component P0.8 was attenuated by a lesion of the eighth nerve. N1.0, P1.2 and N1.5 were unaffected by lesions of the cochlear nucleus but were affected by lesions of the eighth nerve, suggesting that the eighth nerve was the generator of these components. Except for one lesion of the trapezoid body component P1.7 was only affected by lesions of the cochlear nucleus or eighth nerve, suggesting its origin in one or both of these structures. N2.0 was affected by lesions of the ventral cochlear nucleus, the region of the superior olivary complex and the trapezoid body. P3 was affected by lesions in the region of the superior olivary complex and the trapezoid body. N3 and N4 were affected primarily by lesions of the lateral lemniscus, but also by lesions of the superior olivary complex and trapezoid body. The results suggest that except for the first few components (P0.8, N1.0, P1.2 and N1.5) each of the components has substantial contributions from more than one auditory brain stem structure. Component P0.8 was determined to have substantial contributions from both cochlear microphonic and neural activity. © 1980.

A spatial and temporal analysis of auditory evoked potentials within the brain stem were performed in cats to determine the areas of the brain stem having large amplitude voltage fields, corresponding in latency to each of the components of the scalp-recorded auditory brain stem response (ABR). On the basis of this criterion, the first few components (occurring within 2 msec post-stimulus) were attributed to activity in a single structure, the eighth nerve. In contrast, each of the other components was correlated with large amplitude fields in at least two sites within the brain stem auditory pathways. The findings demonstrate a complex spatial and temporal distribution of electrical events within the auditory brain stem pathways, which preclude any simple one-to-one relationship between a given anatomical site and a particular component of the ABR. The possibility that the determination of the generators might be influenced by filtering of the evoked potentials was also examined. High-pass filtering of the evoked potentials resulted in a modification of the defined generators for only one of the components studied (P4). Filtering had little effect on the components of the scalp-recorded ABR.

Brain stem potentials were recorded from scalp electrode to biphasic square wave electrical stimulation of implanted electrodes in the cochlea of three patients. Reliable potentials could be recorded that appeared 1.5 to 2.0 msec prior to the customary acoustically-evoked brain stem potentials. The effects of variations in electrical stimulus parameters of rate and intensity were measured. Brain stem potentials can provide objective indices of the effectiveness of electrical stimulation of the cochlea in man.

Unitary discharge patterns (peristimulus time histograms or PSTH) and synaptic events were studies with intracellular recording techniques in 164 cat cochlear nucleus cells to steady-frequency tone bursts 250 ms in duration. There were four response types defined on the basis of the shape of the discharge patterns to tones at the characteristic or best frequency. Primarylike units resemble eighth nerve fibres and have a maximum discharge at tone onset, followed by a smooth decline to a steady level of activity. Buildup units have a transient response at tone onset, followed a period of little or not activity before gradually increasing their discharge rate for the remainder of the tone burst. Onset units have an initial burst of spikes at the onset, with little or no activity for the remainder of the tone burst. Pause units have a long latency (10-30 ms) between tone onset and the appearance of low levels of unit activity, which then gradually increase in rate for the remainder of the tone burst. Changes in signal frequency or intensity within the excitatory response area did not modify response patterns of primarylike and onset units, but could evoke primarylike patterns in buildup and pause units. Inhibition manifested by suppression of spontaneous activity and membrane hyperpolarization were of three kinds: 1) in response to signals at the edges of the excitatory response area (i.e., the inhibitory surround) and detected in onset buildup, and pause units but not in primarylike units; 2) occurring at the offset of tones in the excitatory response area and detected in all four types of cochlear nucleus cells; 3) during excitatory tone bursts in onset and buildup units associated with the periods of suppressed unit activity. Membrane hyperpolarization did not accompany the delay in unit activity after tone onset in pause units. Inhibitory events in cochlear nucleus cells provide mechanisms for producing diversity in the temporal pattern of discharges to acoustic signals which may underly the encoding of complex features of sounds.

Responses of 99 cochlear nucleus cells and 24 cochlear nerve fibers were studied with FM signals; 14 cochlear nerve fibers and 57 cochlear nucleus cells were studied at four rates of modulation and several signal intensities. Classification of FM response patterns as symmetrical, asymmetrical, or unidirectional was based on the calculation of a symmetry factor (S), which compared the number of discharges evoked by the ascending and by the descending phases of the FM sweep. Certain FM response patterns could not adequately be described by the symmetry factor along and variables of modulation rate and signal intensity had significant influence. A correspondence was found between the four response classes evoked by a steady-frequency tone burst (primarylike, buildup, onset, and pause) and the FM response pattern. Cochlear nerve fibers showed symmetrical response patterns to FM stimulation. Primarylike units were similar to eighth nerve fibers and generally showed symmetrical FM responses. Occasional eighth nerve fibers and primarylike cells developed asymmetry at the fastest rate of modulation (50 sps). Buildup units showed a variety of response patterns to FM signals. Onset units generally showed asymmetrical response patterns with the greater response occurring to the ascending than to the descending phase of the FM sweep. Pause units showed a characteristic inhibition of activity at 5 sps (rate-dependent inhibition). Of the 57 cochlear nuclear cells studied in response to FM signals, 16 were symmetrical, another 16 were symmetrical except at the fastest modulation rate, 12 were asymmetrical, 3 were unidirectional, and 10 showed complex responses to certain signal rates or intensities. It is clear the the cat cochlear with its complex cytoarchitecture is involved in the recoding of acoustic information. Some units in cochlear nucleus demonstrate differential responses to the direction and to the rate of frequency movement. Other cochlear nucleus cells respond as eighth nerve fibers and may serve as simple "relays" in transmitting information from the cochlea to higher auditory centers.

Discrete lesions of the brain stem auditory pathway in cats were found to have complex effects on the auditory brain stem response (ABR). These effects ranged from an amplitude change on only a single component of the ABR to latency and amplitude changes for that component plus some or all of the subsequent components. Lesions of certain portions of the classical primary auditory pathway (i.e., the dorsal cochlear nucleus, the dorsal acoustic stria, the lateral superior olivary nucleus, the posterior portion of the lateral lemniscus and the inferior colliculus) were not associated with changes in the ABR prior to component P5. Except for midline lesions, the effects of a brain stem lesion on the ABR were quite different for ipsilateral and contralateral stimulation. The predominant effect of brain stem lesions on the ABR was an attenuation of the amplitudes of the components and only an occasional increase in their latency. Opposite effects, i.e., increases in amplitude or decreases in latency, were rare. The acute effects of brain stem lesions on the ABR could be transient and not persist in chronic recordings. The components of the ABR were primarily affected by the following lesions. Component P0.8 was attenuated by a lesion of the eighth nerve. N1.0, P1.2 and N1.5 were unaffected by lesions of the cochlear nucleus but were affected by lesions of the eighth nerve, suggesting that the eighth nerve was the generator of these components. Except for one lesion of the trapezoid body component P1.7 was only affected by lesions of the cochlear nucleus or eighth nerve, suggesting its origin in one or both of these structures. N2.0 was affected by lesions of the ventral cochlear nucleus, the region of the superior olivary complex and the trapezoid body. P3 was affected by lesions in the region of the superior olivary complex and the trapezoid body. N3 and N4 were affected primarily by lesions of the lateral lemniscus, but also by lesions of the superior olivary complex and trapezoid body. The results suggest that except for the first few components (P0.8, N1.0, P1.2 and N1.5) each of the components has substantial contributions from more than one auditory brain stem structure. Component P0.8 was determined to have substantial contributions from both cochlear microphonic and neural activity. © 1980.

A spatial and temporal analysis of auditory evoked potentials within the brain stem were performed in cats to determine the areas of the brain stem having large amplitude voltage fields, corresponding in latency to each of the components of the scalp-recorded auditory brain stem response (ABR). On the basis of this criterion, the first few components (occurring within 2 msec post-stimulus) were attributed to activity in a single structure, the eighth nerve. In contrast, each of the other components was correlated with large amplitude fields in at least two sites within the brain stem auditory pathways. The findings demonstrate a complex spatial and temporal distribution of electrical events within the auditory brain stem pathways, which preclude any simple one-to-one relationship between a given anatomical site and a particular component of the ABR. The possibility that the determination of the generators might be influenced by filtering of the evoked potentials was also examined. High-pass filtering of the evoked potentials resulted in a modification of the defined generators for only one of the components studied (P4). Filtering had little effect on the components of the scalp-recorded ABR.

MOST NEUROPHYSIOLOGICAL EXPERIMENTS deal with phenomena which lastfor only a brief period of time, usually measured in milliseconds or seconds.Commonplace subjective experience, however, indicates that longer lastingeffects may follow prolonged periods of sensory stimulation, Sensations ofmotion, for example, may last for hours or days following a rough sea voyage(for a vivid description of this effect see ref. 17). The French refer tothis as ma1 de debarquement. Analogously persisting aftereffects are observedin the visual system (e.g., the “waterfall effect”) and auditory andsomesthetic systems. We presume that neurophysiological events mustunderlie these illusions.The present experiments were designed to record electrical activity takingplace along the auditory pathway before, during, and after prolongedsound stimulation, in order to observe whatever neurophysiological aft,ereffectsmay follow long-lasting stimulation. In addition to aftereffects, wefound other phenomena which merit analysis in their own right.

ALL OF TIIE vmth NERVE FIBERS originatingin the coch lea terminate in the cochlear nucleus,the first central station of the auditorypathway. Extracellular recordings fromunits in this nucleus have shown a diversityof both spontaneous and tone-evoked activitiescompared to activity in Vlllth nervefibers. Tone-evoked inhibition of spontaneousactivity occurs with certainty in thecochlear nucleus (8, 9, 12), but has not beensecurely demonstrated in VIIlth nerve (5,9, 10, 18, 22), and response patterns tosteady tones are quite varied in cochlearnucleus (15), whereas a single response patterncharacterizes VIII th nerve fibers (I 0).The synaptic events in cochlear nucleusthat accompany acoustic stimulation haveonly recently begun to be explored (4, 6).The present study utilizes intracellular recordingsand stimulating techniques in thecochlear nucleus to further delineate thesynaptic basis for central processing of auditorysignals.

THE OLIVOCOCHLEAR BUNDLE (OCB) is knownto modify afferent auditory input at thecochlea. Electrical stimulation of the bundlein the floor of the IVth ventricle causes a suppressionof neural response to clicks recordedat the cochlea (lo), and a paradoxical enhancementof microphonics (8). Fex (8) and,more recently, Wiederhold (23) have shownthat both spontaneous and tone-evoked activitiesof single units in the VIIIth nerve aresimilarly suppressed during such OCB stim-/ Jwhile the carotid arteries were ligated, a trephineulation. The purpose of the present study wasto investigate the effects of OCB stimulationon spontaneous and tone-evoked activities ofsingle units in cochlear nucleus, the first centralauditory station receiving cochlear input.Rasmussen’s finding that OCB collateralsterminate in cochlear nucleus (1 S), raises thepossibility that this efferent system may havea central regulatory role as well. Our resultsindicate that OCB stimulation can modifycochlear nucleus units in a variety of ways.Al though suppression of spontaneous activitywas frequently observed, there were manyunits in which OCB stimulation affected anincrease in spontaneous discharge rates.Furthermore, the effects of OCB stimulationon tone-evoked responses were found to vary with tone intensity in complex ways.

We have investigated the frequency following response (FFR) to pure tones in the cochlear nucleus of anesthetized cats with regard to the spatial distribution of amplitude and phase. Amplitude distributions were variable from animal to animal and showed a range of responses including single and multiple peaks and nulls, broad plateaus, and gradually tapering slopes. In general, amplitudes were larger in the ventral cochlear nucleus and VIIIth nerve than in dorsal cochlear nucleus. Phase distributions displayed gradual phase shifts across the nucleus as well as abrupt phase changes in the order of 0.5 cycle. Stimulus frequency had a greater effect upon the dorso-ventral profile of both phase and amplitude of the FFR than did the horizontal position of the electrode track within the cochlear nucleus. Changing stimulus intensity altered the amplitude profile of the FFR at a given frequency but had relatively little effect upon the phase distribution. Our data are consistent with the following hypotheses: (1) the FFR is generated as an envelope of the VIIIth nerve action potentials as the nerve arborizes and terminates in the cochlear nucleus. Phase shifts may be caused by traveling action potentials along the nerve and/or by volume conduction from different fiber bundles to regions lying between these bundles; (2) the FFR is generated postsynaptically in cochlear nucleus cells innervated by the VIIIth nerve. Once again, phase shifts may reflect the sequential innervation of adjacent dendrites, a 'traveling' postsynaptic wave, or the response of a few generators at different loci driven at different phases, in which case spatial phase shifts are caused by the summing of responses as currents are volume conducted to the recording electrode. © 1967.

Cats with chronically implanted electrodes were used to study changes in the auditory pathway during the wake/sleep cycle. Evoked responses to electrical stimulation of brain stem and thalamic nuclei were recorded and the animals' state of arousal was determined by observation and by monitoring EEG and EMG. Evoked responses in superior olive and inferior colliculus were invariant during the wake/sleep cycle. Evoked responses in medial geniculate and auditory radiations showed significant changes in slow wave sleep compared with wakefulness when stimulated from nuclei below inferior colliculus. However, with inferior colliculus stimulation, no significant changes in response at medial geniculate or radiations were observed. Evoked responses recorded from posterior A1 cortical sites showed increased amplitude of the late wave and simplification of the early biphasic waves during slow wave sleep. In contrast, evoked responses recorded from Ep and anterior A1 sites decreased in amplitude or were absent during slow wave sleep compared to responses recorded during wakefulness. No significant differences between evoked responses recorded at cortex during wake or REM sleep were obtained. It is suggested that in the auditory system, the major changes occurring during the wake/sleep cycle are cortical in origin, and sub-areas of auditory cortex change differentially. Some change is also observed in medial geniculate only if stimulation is below the level of inferior colliculus. © 1971.

A PERIOD OF SENSORY STIMULATION may alter the perception of subsequentsensory events. After sounds, for example, there may be changes in threshold(19), in the quality of acoustic sensation (20, 29), or tinnitus (20). Theneurophysiological mechanisms underlying these alterations in sensation arenot well understood. Working with cats, Starr and Livingston (30) describeda profound and reversible suppression of summated spontaneous activity insubcortical stations of the auditory pathway as an aftereffect of sustainedsound exposure. The period of altered spontaneous activity lengthened asthe intensity or duration of the sound was increased. The experiments onsingle units in cochlear nucleus presented in this report were undertaken todefine more precisely the relationship between the physical parameters ofthe sound stimulus and the period of altered spontaneous activity.

Cats with chronically implanted electrodes were used to study changes in the auditory pathway during the wake/sleep cycle. Evoked responses to electrical stimulation of brain stem and thalamic nuclei were recorded and the animals' state of arousal was determined by observation and by monitoring EEG and EMG. Evoked responses in superior olive and inferior colliculus were invariant during the wake/sleep cycle. Evoked responses in medial geniculate and auditory radiations showed significant changes in slow wave sleep compared with wakefulness when stimulated from nuclei below inferior colliculus. However, with inferior colliculus stimulation, no significant changes in response at medial geniculate or radiations were observed. Evoked responses recorded from posterior A1 cortical sites showed increased amplitude of the late wave and simplification of the early biphasic waves during slow wave sleep. In contrast, evoked responses recorded from Ep and anterior A1 sites decreased in amplitude or were absent during slow wave sleep compared to responses recorded during wakefulness. No significant differences between evoked responses recorded at cortex during wake or REM sleep were obtained. It is suggested that in the auditory system, the major changes occurring during the wake/sleep cycle are cortical in origin, and sub-areas of auditory cortex change differentially. Some change is also observed in medial geniculate only if stimulation is below the level of inferior colliculus. © 1971.