Loudness adaptation accompanying ribbon synapse and auditory nerve disorders.

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.

Auditory cortical N100 in pre- and post-synaptic auditory neuropathy to frequency or intensity changes of continuous tones.

OBJECTIVES: Auditory cortical N100s were examined in ten auditory neuropathy (AN) subjects as objective measures of impaired hearing. METHODS: Latencies 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). RESULTS: AN 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. CONCLUSIONS: As 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. SIGNIFICANCE: Abnormalities 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.

A comparison of auditory evoked potentials to acoustic beats and to binaural beats.

The purpose of this study was to compare cortical brain responses evoked by amplitude modulated acoustic beats of 3 and 6 Hz in tones of 250 and 1000 Hz with those evoked by their binaural beats counterparts in unmodulated tones to indicate whether the cortical processes involved differ. Event-related potentials (ERPs) were recorded to 3- and 6-Hz acoustic and binaural beats in 2000 ms duration 250 and 1000 Hz tones presented with approximately 1 s intervals. Latency, amplitude and source current density estimates of ERP components to beats-evoked oscillations were determined and compared across beat types, beat frequencies and base (carrier) frequencies. All stimuli evoked tone-onset components followed by oscillations corresponding to the beat frequency, and a subsequent tone-offset complex. Beats-evoked oscillations were higher in amplitude in response to acoustic than to binaural beats, to 250 than to 1000 Hz base frequency and to 3 Hz than to 6 Hz beat frequency. Sources of the beats-evoked oscillations across all stimulus conditions located mostly to left temporal lobe areas. Differences between estimated sources of potentials to acoustic and binaural beats were not significant. The perceptions of binaural beats involve cortical activity that is not different than acoustic beats in distribution and in the effects of beat- and base frequency, indicating similar cortical processing.

Cortical evoked potentials to an auditory illusion: binaural beats.

OBJECTIVE: To define brain activity corresponding to an auditory illusion of 3 and 6Hz binaural beats in 250Hz or 1000Hz base frequencies, and compare it to the sound onset response. METHODS: Event-Related Potentials (ERPs) were recorded in response to unmodulated tones of 250 or 1000Hz to one ear and 3 or 6Hz higher to the other, creating an illusion of amplitude modulations (beats) of 3Hz and 6Hz, in base frequencies of 250Hz and 1000Hz. Tones were 2000ms in duration and presented with approximately 1s intervals. Latency, amplitude and source current density estimates of ERP components to tone onset and subsequent beats-evoked oscillations were determined and compared across beat frequencies with both base frequencies. RESULTS: All stimuli evoked tone-onset P(50), N(100) and P(200) components followed by oscillations corresponding to the beat frequency, and a subsequent tone-offset complex. Beats-evoked oscillations were higher in amplitude with the low base frequency and to the low beat frequency. Sources of the beats-evoked oscillations across all stimulus conditions located mostly to left lateral and inferior temporal lobe areas in all stimulus conditions. Onset-evoked components were not different across stimulus conditions; P(50) had significantly different sources than the beats-evoked oscillations; and N(100) and P(200) sources located to the same temporal lobe regions as beats-evoked oscillations, but were bilateral and also included frontal and parietal contributions. CONCLUSIONS: Neural activity with slightly different volley frequencies from left and right ear converges and interacts in the central auditory brainstem pathways to generate beats of neural activity to modulate activities in the left temporal lobe, giving rise to the illusion of binaural beats. Cortical potentials recorded to binaural beats are distinct from onset responses. SIGNIFICANCE: Brain activity corresponding to an auditory illusion of low frequency beats can be recorded from the scalp.

N100 cortical potentials accompanying disrupted auditory nerve activity in auditory neuropathy (AN): effects of signal intensity and continuous noise.

OBJECTIVE: Auditory 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. METHODS: Subjects 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. RESULTS: N100 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. CONCLUSIONS: N100 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. SIGNIFICANCE: N100 latency to tones may serve as an objective measure of the efficiency of auditory temporal processes.

Intensity changes in a continuous tone: auditory cortical potentials comparison with frequency changes.

OBJECTIVES: To examine auditory cortical potentials in normal-hearing subjects to intensity increments in a continuous pure tone at low, mid, and high frequency. METHODS: Electrical scalp potentials were recorded in response to randomly occurring 100 ms intensity increments of continuous 250, 1000, and 4000 Hz tones every 1.4 s. The magnitude of intensity change varied between 0, 2, 4, 6, and 8 dB above the 80 dB SPL continuous tone. RESULTS: Potentials included N100, P200, and a slow negative (SN) wave. N100 latencies were delayed whereas amplitudes were not affected for 250 Hz compared to 1000 and 4000 Hz. Functions relating the magnitude of the intensity change and N100 latency/amplitude did not differ in their slope among the three frequencies. No consistent relationship between intensity increment and SN was observed. Cortical dipole sources for N100 did not differ in location or orientation between the three frequencies. CONCLUSIONS: The relationship between intensity increments and N100 latency/amplitude did not differ between tonal frequencies. A cortical tonotopic arrangement was not observed for intensity increments. Our results are in contrast to prior studies of brain activities to brief frequency changes showing cortical tonotopic organization. SIGNIFICANCE: These results suggest that intensity and frequency discrimination employ distinct central processes.

Auditory-evoked potentials to frequency increase and decrease of high- and low-frequency tones.

OBJECTIVE: To define cortical brain responses to large and small frequency changes (increase and decrease) of high- and low-frequency tones. METHODS: Event-Related Potentials (ERPs) were recorded in response to a 10% or a 50% frequency increase from 250 or 4000 Hz tones that were approximately 3 s in duration and presented at 500-ms intervals. Frequency increase was followed after 1 s by a decrease back to base frequency. Frequency changes occurred at least 1 s before or after tone onset or offset, respectively. Subjects were not attending to the stimuli. Latency, amplitude and source current density estimates of ERPs were compared across frequency changes. RESULTS: All frequency changes evoked components P(50), N(100), and P(200). N(100) and P(200) had double peaks at bilateral and right temporal sites, respectively. These components were followed by a slow negativity (SN). The constituents of N(100) were predominantly localized to temporo-parietal auditory areas. The potentials and their intracranial distributions were affected by both base frequency (larger potentials to low frequency) and direction of change (larger potentials to increase than decrease), as well as by change magnitude (larger potentials to larger change). The differences between frequency increase and decrease depended on base frequency (smaller difference to high frequency) and were localized to frontal areas. CONCLUSIONS: Brain activity varies according to frequency change direction and magnitude as well as base frequency. SIGNIFICANCE: The effects of base frequency and direction of change may reflect brain networks involved in more complex processing such as speech that are differentially sensitive to frequency modulations of high (consonant discrimination) and low (vowels and prosody) frequencies.

Frequency changes in a continuous tone: auditory cortical potentials.

OBJECTIVE: We examined auditory cortical potentials in normal hearing subjects to spectral changes in continuous low and high frequency pure tones. METHODS: Cortical potentials were recorded to increments of frequency from continuous 250 or 4000Hz tones. The magnitude of change was random and varied from 0% to 50% above the base frequency. RESULTS: Potentials consisted of N100, P200 and a slow negative wave (SN). N100 amplitude, latency and dipole magnitude with frequency increments were significantly greater for low compared to high frequencies. Dipole amplitudes were greater in the right than left hemisphere for both base frequencies. The SN amplitude to frequency changes between 4% and 50% was not significantly related to the magnitude of spectral change. CONCLUSIONS: Modulation of N100 amplitude and latency elicited by spectral change is more pronounced with low compared to high frequencies. SIGNIFICANCE: These data provide electrophysiological evidence that central processing of spectral changes in the cortex differs for low and high frequencies. Some of these differences may be related to both temporal- and spectral-based coding at the auditory periphery. Central representation of frequency change may be related to the different temporal windows of integration across frequencies.

Neural and receptor cochlear potentials obtained by transtympanic electrocochleography in auditory neuropathy.

OBJECTIVE: Transtympanic electrocochleography (ECochG) was recorded bilaterally in children and adults with auditory neuropathy (AN) to evaluate receptor and neural generators. METHODS: Test stimuli were clicks from 60 to 120dB p.e. SPL. Measures obtained from eight AN subjects were compared to 16 normally hearing children. RESULTS: Receptor 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. CONCLUSIONS: Three 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. SIGNIFICANCE: Cochlear potential measures may identify pre- and post-synaptic disorders of inner hair cells and auditory nerves in AN.

The auditory P50 component to onset and offset of sound.

OBJECTIVE: The auditory Event-Related Potentials (ERP) of component P50 to sound onset and offset have been reported to be similar, but their magnetic homologue has been reported absent to sound offset. We compared the spatio-temporal distribution of cortical activity during P50 to sound onset and offset, without confounds of spectral change. METHODS: ERPs were recorded in response to onsets and offsets of silent intervals of 0.5 s (gaps) appearing randomly in otherwise continuous white noise and compared to ERPs to randomly distributed click pairs with half second separation presented in silence. Subjects were awake and distracted from the stimuli by reading a complicated text. Measures of P50 included peak latency and amplitude, as well as source current density estimates to the clicks and sound onsets and offsets. RESULTS: P50 occurred in response to noise onsets and to clicks, while to noise offset it was absent. Latency of P50 was similar to noise onset (56 ms) and to clicks (53 ms). Sources of P50 to noise onsets and clicks included bilateral superior parietal areas. In contrast, noise offsets activated left inferior temporal and occipital areas at the time of P50. Source current density was significantly higher to noise onset than offset in the vicinity of the temporo-parietal junction. CONCLUSIONS: P50 to sound offset is absent compared to the distinct P50 to sound onset and to clicks, at different intracranial sources. P50 to stimulus onset and to clicks appears to reflect preattentive arousal by a new sound in the scene. Sound offset does not involve a new sound and hence the absent P50. SIGNIFICANCE: Stimulus onset activates distinct early cortical processes that are absent to offset.

The N1 complex to gaps in noise: effects of preceding noise duration and intensity.

OBJECTIVE: To study the effects of duration and intensity of noise that precedes gaps in noise on the N-Complex (N(1a) and N(1b)) of Event-Related Potentials (ERPs) to the gaps. METHODS: ERPs were recorded from 13 normal subjects in response to 20 ms gaps in 2-4.5 s segments of binaural white noise. Within each segment, the gaps appeared after 500, 1500, 2500 or 4000 ms of noise. Noise intensity was either 75, 60 or 45 dBnHL. Analysis included waveform peak measurements and intracranial source current density estimations, as well as statistical assessment of the effects of pre-gap noise duration and intensity on N(1a) and N(1b) and their estimated intracranial source activity. RESULTS: The N-Complex was detected at about 100 ms under all stimulus conditions. Latencies of N(1a) (at approximately 90 ms) and N(1b) (at approximately 150 ms) were significantly affected by duration of the preceding noise. Both their amplitudes and the latency of N(1b) were affected by the preceding noise intensity. Source current density was most prominent, under all stimulus conditions, in the vicinity of the temporo-parietal junction, with the first peak (N(1a)) lateralized to the left hemisphere and the second peak (N(1b)) - to the right. Additional sources with lower current density were more anterior, with a single peak spanning the duration of the N-Complex. CONCLUSIONS: The N(1a) and N(1b) of the N-Complex of the ERPs to gaps in noise are affected by both duration and intensity of the pre-gap noise. The minimum noise duration required for the appearance of a double-peaked N-Complex is just under 500 ms, depending on noise intensity. N(1a) and N(1b) of the N-Complex are generated predominantly in opposite temporo-parietal brain areas: N(1a) on the left and N(1b) on the right. SIGNIFICANCE: Duration and intensity interact to define the dual peaked N-Complex, signaling the cessation of an ongoing sound.

Cholinesterase inhibitors affect brain potentials in amnestic mild cognitive impairment.

Amnestic mild cognitive impairment (MCI) is an isolated episodic memory disorder that has a high likelihood of progressing to Alzheimer's disease. Auditory sensory cortical responses (P50, N100) have been shown to be increased in amplitude in MCI compared to older controls. We tested whether (1) cortical potentials to other sensory modalities (somatosensory and visual) were also affected in MCI and (2) cholinesterase inhibitors (ChEIs), one of the therapies used in this disorder, modulated sensory cortical potentials in MCI. Somatosensory cortical potentials to median nerve stimulation and visual cortical potentials to reversing checkerboard stimulation were recorded from 15 older controls and 15 amnestic MCI subjects (single domain). Results were analyzed as a function of diagnosis (Control, MCI) and ChEIs treatment (Treated MCI, Untreated MCI). Somatosensory and visual potentials did not differ significantly in amplitude in MCI subjects compared to controls. When ChEIs use was considered, somatosensory potentials (N20, P50) but not visual potentials (N70, P100, N150) were of larger amplitude in untreated MCI subjects compared to treated MCI subjects. Three individual MCI subjects showed increased N20 amplitude while off ChEIs compared to while on ChEIs. An enhancement of N20 somatosensory cortical activity occurs in amnestic single-domain MCI and is sensitive to modulation by ChEIs.

Auditory temporal processes in normal-hearing individuals and in patients with auditory neuropathy.

OBJECTIVE: To study objectively auditory temporal processing in a group of normal hearing subjects and in a group of hearing-impaired individuals with auditory neuropathy (AN) using electrophysiological and psychoacoustic methods. METHODS: Scalp recorded evoked potentials were measured to brief silent intervals (gaps) varying between 2 and 50ms embedded in continuous noise. Latencies and amplitudes of N100 and P200 were measured and analyzed in two conditions: (1) active, when using a button in response to gaps; (2) passive, listening, but not responding. RESULTS: In normal subjects evoked potentials (N100/P200 components) were recorded in response to gaps as short as 5ms in both active and passive conditions. Gap evoked potentials in AN subjects appeared only with prolonged gap durations (10-50ms). There was a close association between gap detection thresholds measured psychoacoustically and electrophysiologically in both normals and in AN subjects. CONCLUSIONS: Auditory cortical potentials can provide objective measures of auditory temporal processes. SIGNIFICANCE: The combination of electrophysiological and psychoacoustic methods converged to provide useful objective measures for studying auditory cortical temporal processing in normals and hearing-impaired individuals. The procedure used may also provide objective measures of temporal processing for evaluating special populations such as children who may not be able to provide subjective responses.

Perceptual consequences of disrupted auditory nerve activity.

Perceptual consequences of disrupted auditory nerve activity were systematically studied in 21 subjects who had been clinically diagnosed with auditory neuropathy (AN), a recently defined disorder characterized by normal outer hair cell function but disrupted auditory nerve function. Neurological and electrophysical evidence suggests that disrupted auditory nerve activity is due to desynchronized or reduced neural activity or both. Psychophysical measures showed that the disrupted neural activity has minimal effects on intensity-related perception, such as loudness discrimination, pitch discrimination at high frequencies, and sound localization using interaural level differences. In contrast, the disrupted neural activity significantly impairs timing related perception, such as pitch discrimination at low frequencies, temporal integration, gap detection, temporal modulation detection, backward and forward masking, signal detection in noise, binaural beats, and sound localization using interaural time differences. These perceptual consequences are the opposite of what is typically observed in cochlear-impaired subjects who have impaired intensity perception but relatively normal temporal processing after taking their impaired intensity perception into account. These differences in perceptual consequences between auditory neuropathy and cochlear damage suggest the use of different neural codes in auditory perception: a suboptimal spike count code for intensity processing, a synchronized spike code for temporal processing, and a duplex code for frequency processing. We also proposed two underlying physiological models based on desynchronized and reduced discharge in the auditory nerve to successfully account for the observed neurological and behavioral data. These methods and measures cannot differentiate between these two AN models, but future studies using electric stimulation of the auditory nerve via a cochlear implant might. These results not only show the unique contribution of neural synchrony to sensory perception but also provide guidance for translational research in terms of better diagnosis and management of human communication disorders.

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

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

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

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