Tinnitus suppression with threshold and subthreshold sound stimuli

In this preliminary report, we present the results from our investigation of 34 tinnitus patients for tinnitus suppression with frequency-specific sound stimuli within the auditory spectrum. Of this number, 22 (64.7%) experienced suppression, 5 (14.7%) had partial suppression, and 7 (20.6%) were nonresponders. Suppression of peripheral tinnitus may result when mechanosensitive outer hair cells are recruited by sound stimuli that can remain at subthreshold level. The suppression mechanism is possibly explained by the electromodel of the auditory system. This physiological model could be the basis of tinnitus suppression therapy in which a low-intensity, frequency-specific and tinnitus-suppressing sound stimulus is introduced instead of a wide-band masking noise.     

Behavioral Evidence for Possible Simultaneous Induction of Hyperacusis and Tinnitus Following Intense Sound Exposure

Many human subjects suffering from chronic tinnitus also suffer from hyperacusis, a heightened perception of loudness at moderate to intense sound levels. While numerous studies suggest that animals develop chronic tinnitus following intense noise exposure, it is not yet clear whether sound exposure also induces chronic hyperacusis-like responses in animals. We addressed this question by examining the chronic effects of intense sound exposure on the acoustic startle response (ASR) and its suppression by background noise containing brief gaps. We compared startle amplitudes in intense tone-exposed (10 kHz, 115 dB SPL, 4 h) and age-matched controls at 2–28 weeks post-exposure. While both groups showed similar startle thresholds, exposed animals showed a hyperacusis-like augmentation of ASR at high stimulus levels. Addition of background noise had little effect on ASR in controls but had a strong suppressive effect on startle in exposed animals, indicating a sensitization to background noise. When the background noise contained a gap preceding the startle stimulus, ASR was suppressed in control animals, but exposed animals showed a marked weakening of gap-induced suppression of ASR. This weakening of gap-induced startle suppression is consistent with the interpretation that the gap may have been masked by tinnitus. The associated hyper-responsiveness to startle stimuli presented alone and the sensitization to background noise suggest that hyperacusis may have also been induced. The results indicate that noise exposure leads to increases in the gain of auditory responsiveness and may offer a model of the association of hyperacusis with tinnitus.     

Neurophysiologic mechanisms of tinnitus

Research over the past decade has provided new insights into the neural mechanisms likely to produce the false percepts of sound associated with tinnitus. These insights have emerged mainly as a result of electrophysiologic studies, examining changes in brain activity, and behavioral studies, examining changes in perception, in animals that have been treated with well-known tinnitus inducers such as salicylates, quinine, and intense sound. The available evidence, based on electrophysiologic studies, suggests that tinnitus is associated with disturbances in spontaneous neural activity in the auditory system. These abnormalities include increases in spontaneous activity (hyperactivity), changes in the timing of neural discharges (i.e., the temporal firing properties of neurons), and an increase in bursting activity of neurons. Parallel studies using behavioral testing methods have demonstrated that agents, which produce these neural changes, also cause tinnitus in animals. This article reviews the literature concerned with both behavioral evidence for tinnitus in animal models and the associated changes that occur at peripheral and central levels of the auditory system.     

Development of hyperactivity after hearing loss in a computational model of the dorsal cochlear nucleus depends on neuron response type

Cochlear damage can change the spontaneous firing rates of neurons in the dorsal cochlear nucleus (DCN). Increased spontaneous firing rates (hyperactivity) after acoustic trauma have been observed in the DCN of rodents such as hamsters, chinchillas and rats. This hyperactivity has been interpreted as a neural correlate of tinnitus. In cats, however, the spontaneous firing rates of DCN neurons were not significantly elevated after acoustic trauma. Species-specific spontaneous firing rates after cochlear damage might be attributable to differences in the response types of DCN neurons: In gerbils, type III response characteristics are predominant, whereas in cats type IV responses are more frequent. To address the question of how the development of hyperactivity after cochlear damage depends on the response type of DCN neurons, we use a computational model of the basic circuit of the DCN. By changing the strength of two types of inhibition, we can reproduce salient features of the responses of DCN neurons. Simulated cochlear damage, which decreases the activity of auditory nerve fibers, is assumed to activate homeostatic plasticity in projection neurons (PNs) of the DCN. We find that the resulting spontaneous firing rates depend on the response type of DCN PNs: PNs with type III and type IV-T response characteristics may become hyperactive, whereas type IV PNs do not develop increased spontaneous firing rates after acoustic trauma. This theoretical framework for the mechanisms and circumstances of the development of hyperactivity in central auditory neurons might also provide new insights into the development of tinnitus.     

Response profiles of auditory cortical neurons to tones and noise in behaving macaque monkeys

The primate auditory cortex is anatomically divided into several areas, but little is known about the functional differences between these areas. Similarly, although neurons in sub-cortical auditory areas of other species have been classified into distinct categories, these criteria have not been applied in primates. This study measured the responses of single neurons in the primary auditory cortex (AI) and the caudomedial field (CM) to tones and noise. Most neurons could be qualitatively classified as onset, sustained, or sustained-onset, but never as primary (VIII nerve)-like or chopper. Quantitative analysis showed a continuum of response types, from having only onset responses to responding throughout the stimulus period. AI neurons had higher firing rates that CM neurons, but CM neurons had higher firing rates to noise stimuli compared to tone stimuli, and a greater percentage of CM neurons had excitatory responses after stimulus offset. There were no differences in the percentage of neurons that had tonic or inhibitory responses. These results indicate that the responses of neurons in the primate auditory cortex are better described as a continuum rather than as discrete classes, and provide further evidence that auditory information is processed in series between AI and CM in the primate.     

Residual Inhibition Functions Overlap Tinnitus Spectra and the Region of Auditory Threshold Shift

Animals exposed to noise trauma show augmented synchronous neural activity in tonotopically reorganized primary auditory cortex consequent on hearing loss. Diminished intracortical inhibition in the reorganized region appears to enable synchronous network activity that develops when deafferented neurons begin to respond to input via their lateral connections. In humans with tinnitus accompanied by hearing loss, this process may generate a phantom sound that is perceived in accordance with the location of the affected neurons in the cortical place map. The neural synchrony hypothesis predicts that tinnitus spectra, and heretofore unmeasured “residual inhibition functions” that relate residual tinnitus suppression to the center frequency of masking sounds, should cover the region of hearing loss in the audiogram. We confirmed these predictions in two independent cohorts totaling 90 tinnitus subjects, using computer-based tools designed to assess the psychoacoustic properties of tinnitus. Tinnitus spectra and residual inhibition functions for depth and duration increased with the amount of threshold shift over the region of hearing impairment. Residual inhibition depth was shallower when the masking sounds that were used to induce residual inhibition showed decreased correspondence with the frequency spectrum and bandwidth of the tinnitus. These findings suggest that tinnitus and its suppression in residual inhibition depend on processes that span the region of hearing impairment and not on mechanisms that enhance cortical representations for sound frequencies at the audiometric edge. Hearing thresholds measured in age-matched control subjects without tinnitus implicated hearing loss as a factor in tinnitus, although elevated thresholds alone were not sufficient to cause tinnitus.

Post-stimulatory suppression, facilitation and tuning for delays shape responses of inferior colliculus neurons to sequential pure tones.

Temporal changes in the excitability of inferior colliculus (IC) neurons will shape their responses to complex stimuli. Single-unit responses of rat IC neurons to the second (probe) of a pair of tones exhibited suppression, facilitation and delay tuned effects. Responses to probe tones were markedly suppressed (by 76% for contralateral stimulation with equal intensity tone pairs) during contralateral and binaural stimulation in 60% of IC neurons. Suppression developed rapidly as a function of the duration of the initial tone, and approached maximum for tones of less than 200 ms. Suppression decreased as the interval between tones increased, and this recovery of responsiveness was often exponential (time constants: mean: 271.4 ms; median: 72.8 ms; n = 47), and independent of the duration and intensity of preceding stimulation. Facilitation of responses to probe tones was observed chiefly in neurons with 'pauser/buildup' response patterns, and decreased as the intertone interval increased. The greatest suppression of responses to probe tones occurred only after intertone intervals of 32 ms (delayed minimum; n = 8) in 11% of IC neurons. Other IC neurons exhibited an increased excitability to probe tones presented 128 ms after stimulation (delayed maximum; n = 7). The latencies of the later neurons' responses were longer (mean: 29.5 ms) than other IC neurons. The role of suppression in sound localization and echo suppression, and the relationship between 'delay tuning' effects and encoding of complex stimuli are discussed.     

The role of GABAergic inhibition in shaping the response size and duration selectivity of bat inferior collicular neurons to sound pulses in rapid sequences

Natural sounds, such as vocal communication sounds of many animal species typically occur as sequential sound pulses. Therefore, the response size of auditory neurons to a sound pulse would be inevitably affected when the sound pulse is preceded and succeeded by another sound pulse (i.e., forward and backward masking). The present study presents data to show that increasing strength of GABAergic inhibition relative to excitation contributes to decreasing response size and sharpening of duration selectivity of bat inferior collicular (IC) neurons to sound pulses in rapid sequences. The response size in number of impulses and duration selectivity of IC neurons were studied with a pulse train containing 9 sound pulses. A family of duration tuning curves was plotted for IC neurons using the number of impulses discharged to each presented sound pulse against pulse duration. Our data show that the response size of IC neurons progressively decreased and duration selectivity increased when determined with sequentially presented sound pulses. This variation in the response size and duration selectivity of IC neurons with sequentially presented sound pulses was abolished or reduced during bicuculline and GABA application. Bicuculline application increased the response size and broadened the duration tuning curve of IC neurons while GABA application produced opposite results. Possible mechanisms underlying increasing strength of GABAergic inhibition with sequentially presented sound pulses are presented. Biological significance of these findings in relation to acoustic signal processing is also discussed.     

Excitation and suppression of primary auditory fibres in the pigeon

Spike potentials were recorded from single fibres in the auditory nerve of the pigeon. In fibres with recognizable responses to sound, spontaneous activity and properties of responses to tonal stimuli were studied in quiet background conditions. Mean spontaneous rate in the sample of fibres was 35 spikes/s. Tuning of spike response to tones was manifest as a single peak in rate at each sound pressure level (SPL) in the frequency-intensity plane. The majority of fibres showed only excitation of spike rate above spontaneous rate. Post stimulus time histograms (PSTs) in such cases were typical of excitatory responses, previously described in birds and mammals showing pronounced adaptation and post-stimulus suppression of spike rate. In most cases of excitation-only responses, however, slopes of rate functions depended on stimulus frequency. Close to characteristic frequency (CF), slopes tended to decrease with increasing SPL, whereas away from CF, slopes tended to increase with SPL. In a minority of excitation-only responses, slopes of rate functions were parallel. In some fibres, tones adjacent to the response area caused overt suppression of spontaneous firing. For these fibres, the slopes of rate functions were more-strongly frequency-dependent, being negative at low SPL when rate suppression occurred. Suppression of spontaneous activity at low SPL was non-monotonic and quite different from suppression of spike rate at stimulus intensities above rat saturation. In PSTs of suppressed spontaneous activity, rebound occurred at the termination of the tone. The results clarify previous observations of suppression of primary auditory responses in birds. We conclude that responses in the majority of auditory fibres in the pigeon are the product of opposing excitatory and suppressive influences in the cochlea, generated by single tones in quite.     

Dopamine Modulates Auditory Responses in the Inferior Colliculus in a Heterogeneous Manner

Perception of complex sounds such as speech is affected by a variety of factors, including attention, expectation of reward, physiological state, and/or disorders, yet the mechanisms underlying this modulation are not well understood. Although dopamine is commonly studied for its role in reward-based learning and in disorders, multiple lines of evidence suggest that dopamine is also involved in modulating auditory processing. In this study, we examined the effects of dopamine application on neuronal response properties in the inferior colliculus (IC) of awake mice. Because the IC contains dopamine receptors and nerve terminals immunoreactive for tyrosine hydroxylase, we predicted that dopamine would modulate auditory responses in the IC. We recorded single-unit responses before, during, and after the iontophoretic application of dopamine using piggyback electrodes. We examined the effects of dopamine on firing rate, timing, and probability of bursting. We found that application of dopamine affected neural responses in a heterogeneous manner. In more than 80 % of the neurons, dopamine either increased (32 %) or decreased (50 %) firing rate, and the effects were similar on spontaneous and sound-evoked activity. Dopamine also either increased or decreased first spike latency and jitter in almost half of the neurons. In 3/28 neurons (11 %), dopamine significantly altered the probability of bursting. The heterogeneous effects of dopamine observed in the IC of awake mice were similar to effects observed in other brain areas. Our findings indicate that dopamine differentially modulates neural activity in the IC and thus may play an important role in auditory processing.     

Role of GABA abnormalities in the inferior colliculus pathophysiology - audiogenic seizures

gamma-Aminobutyric acid (GABA), acting at GABA(A) receptors, mediates inhibition in inferior colliculus (IC) central nucleus (ICc) neurons and plays a prominent role in mediating acoustically evoked non-monotonicity, offset inhibition, and binaural inhibition, and is also important in tonic inhibition. The IC plays an important role in a number of pathophysiological conditions that involve hearing, including tinnitus, age-related hearing loss, and audiogenic seizures (AGS). AGS are a major form of rodent neurological disorder that can be genetically mediated and can also be readily induced in both young and mature animals. A deficit in GABA-mediated inhibition in IC neurons has been shown to be a critical mechanism in genetic and induced forms of AGS. Thus, both endogenously evoked GABA-mediated inhibition and exogenously applied GABA are reduced in efficacy in IC neurons of rats that are susceptible to AGS. GABA-mediated inhibition in IC neurons is significantly more easily blocked by a GABA(A) antagonist in genetic and induced forms of AGS in vivo and in vitro. AGS can be induced in normal animals by treatments that reduce the effectiveness of GABA in the IC. Glutamate-mediated excitation is a critical element of neurotransmission in IC neurons, and excessive activation of glutamate receptors in the IC is also strongly implicated as the other major mechanism in the pathophysiology of AGS. These neurotransmitter abnormalities result in excessive firing of ICc neurons that acts as the critical initiation mechanism for triggering seizures in response to intense acoustic stimuli.     

Inhibitory neurotransmission in animal models of tinnitus: maladaptive plasticity

Tinnitus is a phantom auditory sensation experienced by up to 14% of the United States population with a smaller percentage experiencing decreased quality of life. A compelling hypothesis is that tinnitus results from a maladaptive plastic net down-regulation of inhibitory amino acid neurotransmission in the central auditory pathway. This loss of inhibition may be a compensatory response to loss of afferent input such as that caused by acoustic insult and/or age-related hearing loss, the most common causes of tinnitus in people. Compensatory plastic changes may result in pathologic neural activity that underpins tinnitus. The neural correlates include increased spontaneous spiking, increased bursting and decreased variance of inter-spike intervals. This review will examine evidence for chronic plastic neuropathic changes in the central auditory system of animals with psychophysically-defined tinnitus. Neurochemical studies will focus on plastic tinnitus-related changes of inhibitory glycinergic neurotransmission in the adult dorsal cochlear nucleus (DCN). Electrophysiological studies will focus on functional changes in the DCN and inferior colliculus (IC). Tinnitus was associated with increased spontaneous activity and altered response properties of fusiform cells, the major output neurons of DCN. Coincident with these physiologic alterations were changes in glycine receptor (GlyR) subunit composition, its anchoring/trafficking protein, gephyrin and the number and affinity of membrane GlyRs revealed by receptor binding. In the IC, the primary afferent target of DCN fusiform cells, multi-dimensional alterations in unit-spontaneous activity (rate, burst rate, bursting pattern) were found in animals with behavioral evidence of chronic tinnitus more than 9 months following the acoustic/cochlear insult. In contrast, immediately following an intense sound exposure, acute alterations in IC spontaneous activity resembled chronic tinnitus-related changes but were not identical. This suggests that long-term neuroplastic changes responsible for chronic tinnitus are likely to be responsible for its persistence. A clear understanding of tinnitus-related plasticity in the central auditory system and its associated neurochemistry may help define unique targets for therapeutic drug development.     

Temporal integration in the human auditory cortex as represented by the development of the steady-state magnetic field

The threshold for detecting amplitude modulation (AM) decreases with increasing duration of the AM sound up to several hundred milliseconds. If the auditory evoked steady-state response (SSR) to AM sound is an electrophysiological correlate of AM processing in the human brain, the development of the SSR should follow this course of temporal integration. Magnetoencephalographic recordings of SSR to 40 Hz AM tone-bursts were compared with responses to non-modulated tone-bursts at inter-stimulus intervals (ISIs) of 3, 1, and 0.5 s. Both types of stimuli elicited a transient gamma-band response (GBR), an N1 wave, and a sustained field (SF) during stimulus presentation. The AM stimulus evoked an additional 40 Hz SSR. The N1 amplitude was strongly reduced with shortened ISI, whereas the amplitudes of SSR, GBR, and SF were little affected by the ISI. Magnetic source-localization procedures estimated the generators of the early GBR, the SSR, and the SF to be anterior and medial to the sources of the N1. The sources of the SSR were in primary auditory cortex and separate from GBR sources. The SSR amplitude increased monotonically over a 200 ms period beginning about 40 ms after stimulus onset. The time course of the SSR phase reliably measured the duration of this transition to the steady state. At stimulus offset the SSR ceased within 50 ms. These results indicate that the primary auditory cortex responds immediately to stimulus changes and integrates stimulus features over a period of about 200 ms.     

Spontaneous activity in the inferior colliculus of CBA/J mice after manipulations that induce tinnitus

Several physiological studies have linked experimentally induced tinnitus to increases in the spontaneous activity of auditory neurons. These results have led to the proposal of hyperactivity models of tinnitus in which elevated neural activity in the absence of auditory stimulation is perceived as phantom sound. Such models are appealing in their simplicity but remain controversial because a generalized elevation of spontaneous rates may not be observed after treatments that induce tinnitus in humans and experimental animals. Our study addressed these issues by characterizing the effects of common methods of tinnitus induction on spontaneous activity in the central nucleus of the inferior colliculus (ICC). The ICC is an interesting structure in tinnitus research because its diverse inputs include putative generator sites in the dorsal cochlear nucleus, as well as brainstem sources that appear to remain normal after tinnitus induction. Groups of CBA/J mice were subjected to one of three induction methods: bilateral or unilateral sound exposure, and acute salicylate intoxication. Relative to normal baselines, bilaterally exposed mice showed increases in the spontaneous rates of neurons with tuning near the exposure frequency. When the sample was separated into physiologically defined response classes, exposure effects were strongest among neurons with broad excitatory bandwidths. By contrast, salicylate decreased the spontaneous rates of low-frequency neurons with transient sound-evoked activity. Our results suggest that the disordered processes of hearing that give rise to tinnitus do not involve a pervasive elevation of spontaneous activity or a single mode of induction.     

Long-term inhibition of tinnitus by UltraQuiet therapy: preliminary report

Masking of tinnitus by noise can produce residual inhibition, a persistence in the reduction in tinnitus after the noise is removed. Typically, this relief is very short-lived, on the order of minutes. This report highlights long-term inhibition of tinnitus by UltraQuiet therapy, a new technique that employs patterned sound in the 10- to 20-kHz range, presented through bone conduction. Nine subjects participated in a study of the efficacy of this tinnitus suppression technique. Eight reported improvement in tinnitus symptoms; one did not complete the study. The duration of the improvement ranged from days to weeks. This long-term inhibition may involve a truly plastic change in the brain at the central level.     

Residual inhibition functions in relation to tinnitus spectra and auditory threshold shift

CONCLUSIONS: Psychoacoustic functions relating the depth and duration of tinnitus suppression ('residual inhibition') to the center frequency of band-passed noise masking sounds appear to span the region of hearing loss, as do psychoacoustic measurements of the tinnitus spectrum. The results (1) suggest that cortical map reorganization induced by hearing loss is not the principal source of the tinnitus sensation and (2) provide a necessary baseline for optimizing residual inhibition in individual cases. OBJECTIVE: To measure residual inhibition functions and tinnitus spectra using sounds spanning the region of hearing loss. MATERIALS AND METHODS: Three subject-driven, computer-based tools were developed and applied to measure psychoacoustic properties of tinnitus and residual inhibition in 32 subjects with chronic tonal, ringing, or hissing tinnitus. Residual inhibition functions were measured with band-passed noise sounds varying in center frequency up to 12.0 kHz. RESULTS: The depth and duration of residual inhibition increased with the center frequency of the band-passed noise stimuli. Near-elimination of tinnitus for up to 45 s was reported by 8/24 (33%) subjects at center frequencies above 3 kHz (these cases distributed across tinnitus types). Tinnitus spectra covered the region of hearing loss with no preponderance of frequencies near the audiometric edge of normal hearing.     

Noise Enhances Modulation Sensitivity in Cochlear Implant Listeners: Stochastic Resonance in a Prosthetic Sensory System?

Cochlear implants restore auditory sensitivity to the profoundly hearing-impaired by means of electrical stimulation of residual auditory nerve fibers. Sensorineural hearing loss results in a loss of spontaneous activity among the remaining auditory neurons and is accompanied by a reduction in the normal stochastic nature of neural firing in response to electric stimulation. It has been hypothesized that the natural stochasticity of the neural response is important for auditory signal processing and that introducing some optimal amount of noise into the stimulus may improve auditory perception through the implant. In this article we show that, for soft but audible stimuli, an optimal amount of "prosthetic" noise significantly improves sensitivity to envelope modulation in cochlear implant listeners. A nonmonotonic function relates modulation sensitivity and noise level, suggesting the presence of stochastic resonance.     

Effects of Acoustic Environment on Tinnitus Behavior in Sound-Exposed Rats

Laboratory studies often rely on a damaging sound exposure to induce tinnitus in animal models. Because the time course and ultimate success of the induction process is not known in advance, it is not unusual to maintain sound-exposed animals for months while they are periodically assessed for behavioral indications of the disorder. To demonstrate the importance of acoustic environment during this period of behavioral screening, sound-exposed rats were tested for tinnitus while housed under quiet or constant noise conditions. More than half of the quiet-housed rats developed behavioral indications of the disorder. None of the noise-housed rats exhibited tinnitus behavior during 2 months of behavioral screening. It is widely assumed that the “phantom sound” of tinnitus reflects abnormal levels of spontaneous activity in the central auditory pathways that are triggered by cochlear injury. Our results suggest that sustained patterns of noise-driven activity may prevent the injury-induced changes in central auditory processing that lead to this hyperactive state. From the perspective of laboratory studies of tinnitus, housing sound-exposed animals in uncontrolled noise levels may significantly reduce the success of induction procedures. From a broader clinical perspective, an early intervention with sound therapy may reduce the risk of tinnitus in individuals who have experienced an acute cochlear injury.     

Neural representation of sound duration in the inferior colliculus of the mouse

In this study we examined the neuronal responses of single units to different sound durations in the inferior colliculus (IC) of the mouse. One hundred and one recorded units were classified into onset (58%), sustained (9%) on-sustained (22%), pauser (9%) and chopper (2%) response patterns. Thirty-four percent of the recorded units showing stronger responses to long stimulus durations were defined as long-duration-selective neurons. Twenty-five percent of the units preferred a narrow range of sound durations and were classified as band-pass neurons. Ten percent of the units responded preferentially to short stimulus durations and thus displayed short-duration selectivity. Twelve percent of the units that responded with nearly constant spike counts to stimuli of varying duration were classified as all-pass neurons. In contrast to the result of no short-duration-selective neurons found in chinchilla IC, we observed that some of the onset units in the IC of the mouse displayed a short duration preference. The best duration range of the duration-selective neurons in the present study corresponds to the duration range of mouse calls. We suggest that an inhibitory mechanism contributes to the duration selectivity observed in the present study.     

Responses of cochlear nucleus neurons to harmonic and mistuned complex tones

Preliminary measurements of the representation in the cochlear nucleus (CN) of harmonic tones, harmonic tones with mistuned components, and double harmonic tones are reported. These data indicate that, unlike auditory nerve fibers and IC neurons, neurons in the CN may exhibit one of several qualitatively different response patterns when stimulated with mistuned tones. Primary-like neurons synchronized their discharges to 2-3 individual stimulus components, much like auditory nerve fibers do. Chopper neurons tended to respond with the periodicity of envelopes produced by interactions between adjacent stimulus components but exhibited little or no response synchronized to individual stimulus components. A small proportion of CN neurons exhibited complex slowly-modulated discharge patterns similar to those that are commonly observed in the inferior colliculus (IC). The patterns obtained from CN neurons with different pure tone discharge patterns were generally consistent with expectations based on previous studies with other stimuli. The measurements provided additional insight into the hierarchical processing stages that result in the highly patterned responses of IC neurons to harmonic and mistuned tones.