Is the din really harmless? Long-term effects of non-traumatic noise on the adult auditory system.

People are increasingly being exposed to environmental noise from traffic, media and other sources that falls within and outside legal limits. Although such environmental noise is known to cause stress in the auditory system, it is still generally considered to be harmless. This complacency may be misplaced: even in the absence of cochlear damage, new findings suggest that environmental noise may progressively degrade hearing through alterations in the way sound is represented in the adult auditory cortex.

The auditory cortex and tinnitus ­ a review of animal and human studies.

Tinnitus is the sound heard in the absence of physical sound sources external or internal to the body. Tinnitus never occurs in isolation; it typically develops after hearing loss, and not infrequently for losses at the higher frequencies not tested in clinical audiology. Furthermore, tinnitus is often accompanied by hyperacusis, i.e. increased loudness sensitivity, which may reflect the central gain change in the auditory system that occurs after hearing loss. I will first review the electrophysiological findings in the thalamus and cortex pertaining to animal research into tinnitus. This will comprise the changes in tonotopic maps, spontaneous firing rates and changes in pairwise neural cross-correlation induced by tinnitus-inducing agents that are commonly used in animal experiments. These are systemic application of sodium salicylate, and noise exposure at levels ranging from those that do not cause a hearing loss, to those that only cause a temporary threshold shift, to those that cause a permanent hearing loss. Following this, I will review neuroimaging and electrophysiological findings in the auditory cortex in humans with tinnitus. The neural substrates of tinnitus derived from animal data do not apply universally, as neither hearing loss nor hyperacusis appear to be necessary conditions for tinnitus to occur in humans. Finally, I will relate the findings in humans to the predictions from animal models of tinnitus. These comparisons indicate that neural correlates of tinnitus can be studied successfully both at the level of animal models and in humans.

Tinnitus: animal models and findings in humans.

Chronic tinnitus (ringing of the ears) is a medically untreatable condition that reduces quality of life for millions of individuals worldwide. Most cases are associated with hearing loss that may be detected by the audiogram or by more sensitive measures. Converging evidence from animal models and studies of human tinnitus sufferers indicates that, while cochlear damage is a trigger, most cases of tinnitus are not generated by irritative processes persisting in the cochlea but by changes that take place in central auditory pathways when auditory neurons lose their input from the ear. Forms of neural plasticity underlie these neural changes, which include increased spontaneous activity and neural gain in deafferented central auditory structures, increased synchronous activity in these structures, alterations in the tonotopic organization of auditory cortex, and changes in network behavior in nonauditory brain regions detected by functional imaging of individuals with tinnitus and corroborated by animal investigations. Research on the molecular mechanisms that underlie neural changes in tinnitus is in its infancy and represents a frontier for investigation.

Reversible long-term changes in auditory processing in mature auditory cortex in the absence of hearing loss induced by passive, moderate-level sound exposure.

It has become increasingly clear that even occasional exposure to loud sounds in occupational or recreational settings can cause irreversible damage to the hair cells of the cochlea and the auditory nerve fibers, even if the resulting partial loss of hearing sensitivity, usually accompanied by tinnitus, disappears within hours or days of the exposure. Such exposure may explain at least some cases of poor speech intelligibility in noise in the face of a normal or near-normal audiogram. Recent findings from our laboratory suggest that long-term changes to auditory brain function-potentially leading to problems with speech intelligibility-can be effected by persistent, passive exposure to more moderate levels of noise (in the 70 dB SPL range) in the apparent absence of damage to the auditory periphery (as reflected in normal distortion product otoacoustic emissions and auditory brainstem responses). Specifically, passive exposure of adult cats to moderate levels of band-pass-filtered noise, or to band-limited ensembles of dense, random tone pips, can lead to a profound decrease of neural activity in the auditory cortex roughly in the exposure frequency range, and to an increase of activity outside that range. This can progress to an apparent reorganization of the cortical tonotopic map, which is reminiscent of the reorganization resulting from hearing loss restricted to a part of the hearing frequency range, although again, no hearing loss was apparent after our moderate-level sound exposure. Here, we review this work focusing specifically on the potential hearing problems that may arise despite a normally functioning auditory periphery.

Ringing ears: the neuroscience of tinnitus.

Tinnitus is a phantom sound (ringing of the ears) that affects quality of life for millions around the world and is associated in most cases with hearing impairment. This symposium will consider evidence that deafferentation of tonotopically organized central auditory structures leads to increased neuron spontaneous firing rates and neural synchrony in the hearing loss region. This region covers the frequency spectrum of tinnitus sounds, which are optimally suppressed following exposure to band-limited noise covering the same frequencies. Cross-modal compensations in subcortical structures may contribute to tinnitus and its modulation by jaw-clenching and eye movements. Yet many older individuals with impaired hearing do not have tinnitus, possibly because age-related changes in inhibitory circuits are better preserved. A brain network involving limbic and other nonauditory regions is active in tinnitus and may be driven when spectrotemporal information conveyed by the damaged ear does not match that predicted by central auditory processing.

Sound frequency representation in primary auditory cortex is level tolerant for moderately loud, complex sounds.

The distribution of neuronal characteristic frequencies over the area of primary auditory cortex (AI) roughly reflects the tonotopic organization of the cochlea. However, because the area of AI activated by any given sound frequency increases erratically with sound level, it has generally been proposed that frequency is represented in AI not with a rate-place code but with some more complex, distributed code. Here, on the basis of both spike and local field potential (LFP) recordings in the anesthetized cat, we show that the tonotopic representation in AI is much more level tolerant when mapped with spectrotemporally dense tone pip ensembles rather than with individually presented tone pips. That is, we show that the tuning properties of individual unit and LFP responses are less variable with sound level under dense compared with sparse stimulation, and that the spatial frequency resolution achieved by the AI neural population at moderate stimulus levels (65 dB SPL) is better with densely than with sparsely presented sounds. This implies that nonlinear processing in the central auditory system can compensate (in part) for the level-dependent coding of sound frequency in the cochlea, and suggests that there may be a functional role for the cortical tonotopic map in the representation of complex sounds.

Separate auditory pathways for the induction and maintenance of tinnitus and hyperacusis?

Tinnitus and hyperacusis often occur together, however tinnitus may occur without hyperacusis or hyperacusis without tinnitus. Based on animal research one could argue that hyperacusis results from noise exposures that increase central gain in the lemniscal, tonotopically organized, pathways, whereas tinnitus requires increased burst firing and neural synchrony in the extra-lemniscal pathway. However, these substrates are not sufficient and require involvement of the central nervous system. The dominant factors in changing cortical networks in tinnitus patients are foremost the degree and type of hearing loss, and comorbidities such as distress and mood. So far, no definite changes have been established for tinnitus proper, albeit that changes in connectivity between the dorsal attention network and the parahippocampal area, as well as the default-mode network-precuneus decoupling, appear to be strong candidates. I conclude that there is still a strong need for further integrating animal and human research into tinnitus and hyperacusis.

The thalamus and tinnitus: Bridging the gap between animal data and findings in humans.

The neuronal mechanisms underlying tinnitus are yet to be revealed. Tinnitus, an auditory phantom sensation, used to be approached as a purely auditory domain symptom. More recently, the modulatory impact of non-auditory brain regions on the percept and burden of tinnitus are explored. The thalamus is uniquely situated to facilitate the communication between auditory and non-auditory subcortical and cortical structures. Traditionally, animal models of tinnitus have focussed on subcortical auditory structures, and research with human participants has been concerned with cortical activity in auditory and non-auditory areas. Recently, both research fields have investigated the connectivity between subcortical and cortical regions and between auditory and non-auditory areas. We show that even though the different fields employ different methods to investigate the activity and connectivity of brain areas, there is consistency in the results on tinnitus between these different approaches. This consistency between human and animals research is observed for tinnitus with peripherally instigated hearing damage, and for results obtained with salicylate and noise-induced tinnitus. The thalamus integrates input from limbic and prefrontal areas and modulates auditory activity via its connections to both subcortical and cortical auditory areas. Reported altered activity and connectivity of the auditory, prefrontal, and limbic regions suggest a more systemic approach is necessary to understand the origins and impact of tinnitus.

Tinnitus and tinnitus disorder: Theoretical and operational definitions (an international multidisciplinary proposal).

As for hypertension, chronic pain, epilepsy and other disorders with particular symptoms, a commonly accepted and unambiguous definition provides a common ground for researchers and clinicians to study and treat the problem. The WHO's ICD11 definition only mentions tinnitus as a nonspecific symptom of a hearing disorder, but not as a clinical entity in its own right, and the American Psychiatric Association's DSM-V doesn't mention tinnitus at all. Here we propose that the tinnitus without and with associated suffering should be differentiated by distinct terms: "Tinnitus" for the former and "Tinnitus Disorder" for the latter. The proposed definition then becomes "Tinnitus is the conscious awareness of a tonal or composite noise for which there is no identifiable corresponding external acoustic source, which becomes Tinnitus Disorder "when associated with emotional distress, cognitive dysfunction, and/or autonomic arousal, leading to behavioural changes and functional disability.". In other words "Tinnitus" describes the auditory or sensory component, whereas "Tinnitus Disorder" reflects the auditory component and the associated suffering. Whereas acute tinnitus may be a symptom secondary to a trauma or disease, chronic tinnitus may be considered a primary disorder in its own right. If adopted, this will advance the recognition of tinnitus disorder as a primary health condition in its own right. The capacity to measure the incidence, prevalence, and impact will help in identification of human, financial, and educational needs required to address acute tinnitus as a symptom but chronic tinnitus as a disorder.

Nonlinear cross-frequency interactions in primary auditory cortex spectrotemporal receptive fields: a Wiener-Volterra analysis.

The effects of nonlinear interactions between different sound frequencies on the responses of neurons in primary auditory cortex (AI) have only been investigated using two-tone paradigms. Here we stimulated with relatively dense, Poisson-distributed trains of tone pips (with frequency ranges spanning five octaves, 16 frequencies /octave, and mean rates of 20 or 120 pips /s), and examined within-frequency (or auto-frequency) and cross-frequency interactions in three types of AI unit responses by computing second-order "Poisson-Wiener" auto- and cross-kernels. Units were classified on the basis of their spectrotemporal receptive fields (STRFs) as "double-peaked", "single-peaked" or "peak-valley". Second-order interactions were investigated between the two bands of excitatory frequencies on double-peaked STRFs, between an excitatory band and various non-excitatory bands on single-peaked STRFs, and between an excitatory band and an inhibitory sideband on peak-valley STRFs. We found that auto-frequency interactions (i.e., those within a single excitatory band) were always characterized by a strong depression of (first-order) excitation that decayed with the interstimulus lag up to approximately 200 ms. That depression was weaker in cross-frequency compared to auto-frequency interactions for approximately 25% of dual-peaked STRFs, evidence of "combination sensitivity" for the two bands. Non-excitatory and inhibitory frequencies (on single-peaked and peak-valley STRFs, respectively) typically weakly depressed the excitatory response at short interstimulus lags (<50 ms), but weakly facilitated it at longer lags ( approximately 50-200 ms). Both the depression and especially the facilitation were stronger for interactions with inhibitory frequencies rather than just non-excitatory ones. Finally, facilitation in single-peaked and peak-valley units decreased with increasing stimulus density. Our results indicate that the strong combination sensitivity and cross-frequency facilitation suggested by previous two-tone-paradigm studies are much less pronounced when using more temporally-dense stimuli.

Maximum decoding abilities of temporal patterns and synchronized firings: application to auditory neurons responding to click trains and amplitude modulated white noise.

Simultaneous recordings of an increasing number of neurons have recently become available, but few methods have been proposed to handle this activity. Here, we extract and investigate all the possible temporal neural activity patterns based on synchronized firings of neurons recorded on multiple electrodes, or based on bursts of single-electrode activity in cat primary auditory cortex. We apply this to responses to periodic click trains or sinusoïdal amplitude modulated noise by obtaining for each pattern its temporal modulation transfer function. An algorithm that maximizes the mutual information between all patterns and stimuli subsequently leads to the identification of patterns that optimally decode modulation frequency (MF). We show that stimulus information contained in multi-electrode synchronized firing is not redundant with single-electrode firings and leads to improved efficiency of MF decoding. We also show that the combined use of firing rate and temporal codes leads to a better discrimination of the MF.

Spectrotemporal receptive fields in anesthetized cat primary auditory cortex are context dependent.

In order to investigate how the auditory scene is analyzed and perceived, auditory spectrotemporal receptive fields (STRFs) are generally used as a convenient way to describe how frequency and temporal sound information is encoded. However, using broadband sounds to estimate STRFs imperfectly reflects the way neurons process complex stimuli like conspecific vocalizations insofar as natural sounds often show limited bandwidth. Using recordings in the primary auditory cortex of anesthetized cats, we show that presentation of narrowband stimuli not including the best frequency of neurons provokes the appearance of residual peaks and increased firing rate at some specific spectral edges of stimuli compared with classical STRFs obtained from broadband stimuli. This result is the same for STRFs obtained from both spikes and local field potentials. Potential mechanisms likely involve release from inhibition. We thus emphasize some aspects of context dependency of STRFs, that is, how the balance of inhibitory and excitatory inputs is able to shape the neural response from the spectral content of stimuli.

Spectrally enhanced acoustic environment disrupts frequency representation in cat auditory cortex.

Sensory environments are known to shape nervous system organization. Here we show that passive long-term exposure to a spectrally enhanced acoustic environment (EAE) causes reorganization of the tonotopic map in juvenile cat auditory cortex without inducing any hearing loss. The EAE consisted of tone pips of 32 different frequencies (5-20 kHz), presented in random order at an average rate of 96 Hz. The EAE caused a strong reduction of the representation of EAE frequencies and an over-representation of frequencies neighboring those of the EAE. This is in sharp contrast with earlier developmental studies showing an enlargement of the cortical representation of EAEs consisting of a narrow frequency band. We observed fewer than normal appropriately tuned short-latency responses to EAE frequencies, together with more common long-latency responses tuned to EAE-neighboring frequencies.

Oscillations in the auditory system and their possible role.

GOURÉVITCH, B., C. Martin, O. Postal, J.J. Eggermont. Oscillations in the auditory system, their possible role. NEUROSCI BIOBEHAV REV XXX XXX-XXX, 2020. - Neural oscillations are thought to have various roles in brain processing such as, attention modulation, neuronal communication, motor coordination, memory consolidation, decision-making, or feature binding. The role of oscillations in the auditory system is less clear, especially due to the large discrepancy between human and animal studies. Here we describe many methodological issues that confound the results of oscillation studies in the auditory field. Moreover, we discuss the relationship between neural entrainment and oscillations that remains unclear. Finally, we aim to identify which kind of oscillations could be specific or salient to the auditory areas and their processing. We suggest that the role of oscillations might dramatically differ between the primary auditory cortex and the more associative auditory areas. Despite the moderate presence of intrinsic low frequency oscillations in the primary auditory cortex, rhythmic components in the input seem crucial for auditory processing. This allows the phase entrainment between the oscillatory phase and rhythmic input, which is an integral part of stimulus selection within the auditory system.

Increasing spectrotemporal sound density reveals an octave-based organization in cat primary auditory cortex.

Auditory neurons are likely adapted to process complex stimuli, such as vocalizations, which contain spectrotemporal modulations. However, basic properties of auditory neurons are often derived from tone pips presented in isolation, which lack spectrotemporal modulations. In this context, it is unclear how to deduce the functional role of auditory neurons from their tone pip-derived tuning properties. In this study, spectrotemporal receptive fields (STRFs) were obtained from responses to multi-tone stimulus ensembles differing in their average spectrotemporal density (i.e., number of tone pips per second). STRFs for different stimulus densities were derived from multiple single-unit activity (MUA) and local field potentials (LFPs), simultaneously recorded in primary auditory cortex of cats. Consistent with earlier studies, we found that the spectral bandwidth was narrower for MUA compared with LFPs. Both neural firing rate and LFP amplitude were reduced when the density of the stimulus ensemble increased. Surprisingly, we found that increasing the spectrotemporal sound density revealed with increasing clarity an over-representation of response peaks at frequencies of approximately 3, 5, 10, and 20 kHz, in both MUA- and LFP-derived STRFs. Although the decrease in spectral bandwidth and neural activity with increasing stimulus density can likely be accounted for by forward suppression, the mechanisms underlying the over-representation of the octave-spaced response peaks are unclear. Plausibly, the over-representation may be a functional correlate of the periodic pattern of corticocortical connections observed along the tonotopic axis of cat auditory cortex.

Cochlea and auditory nerve.

The transduction process in the cochlea requires patent hair cells. Population responses that reflect this patency are the cochlear microphonic (CM) and summating potential (SP). They can be measured using electrocochleography (ECochG). The CM reflects the sound waveform in the form of outer hair cell (OHC) depolarization and hyperpolarization, and the SP reflects the average voltage difference of the OHC membrane potential for depolarization and hyperpolarization. The CM can be measured using ECochG or via the so-called otoacoustic emissions, using a sensitive microphone in the ear canal. Neural population responses are called the compound action potentials (CAPs), which by frequency selective masking can be decomposed into narrow-band action potentials (NAPs) reflecting CAPs evoked by activity from small cochlear regions. Presence of CM and absence of CAPs are the diagnostic hallmarks of auditory neuropathy. Increased and prolonged SPs are often found in Ménière's disease but are too often in the normal range to be diagnostic. When including NAP waveforms, Ménière's disease can be differentiated from vestibular schwannomas, which often feature overlapping symptoms such as dizziness, hearing loss, and tinnitus. The patency of the efferent system, particularly the olivocochlear bundle, can be tested using the suppressive effect of contralateral stimulation on the otoacoustic emission amplitude.

Auditory brainstem response.

The auditory brainstem response (ABR), consisting of five to six vertex-positive peaks with separation of about 0.8ms, is very sensitive to factors that affect conduction velocity and hence ABR wave latencies in the brainstem auditory pathways. In addition, disorders causing dissynchronization of neural activity result in an amplitude decrease or disappearance of ABR peaks. The opposite effects occur in the maturation process, which takes about 2 years postterm; here conduction velocity increases quickly to its adult value, but synaptic delays being sensitive to synchronous release of transmitter substance take considerably longer. In neurological disorders, those that cause dissynchrony, such as auditory neuropathy and vestibular schwannoma, Gaucher disease, and Krabbe disease, the (longer latency) ABR peaks are reduced or absent. Effects on neural conduction, resulting in increased ABR interwave latencies, are found in vestibular schwannomas, Bell's palsy, Duane retraction syndrome, Marcus Gunn ptosis, and various encephalomyopathies. These measures allow an assessment of the parts of the brainstem that are involved.

Spectro-temporal sound density-dependent long-term adaptation in cat primary auditory cortex.

Sensory systems use adaptive strategies to code for the changing environment on different time scales. Short-term adaptation (up to 100 ms) reflects mostly synaptic suppression mechanisms after response to a stimulus. Long-term adaptation (up to a few seconds) is reflected in the habituation of neuronal responses to constant stimuli. Very long-term adaptation (several weeks) can lead to plastic changes in the cortex, most often facilitated during early development, by stimulus relevance or by behavioral states such as attention. In this study, we show that long-term adaptation with a time course of tens of minutes is detectable in anesthetized adult cat auditory cortex after a few minutes of listening to random-frequency tone pips. After the initial post-onset suppression, a slow recovery of the neuronal response strength to tones at or near their best frequency was observed for low-rate random sounds (four pips per octave per second) during stimulation. The firing rate at the end of stimulation (15 min) reached levels close to that observed during the initial onset response. The effect, visible for both spikes and, to a smaller extent, local field potentials, decreased with increasing spectro-temporal density of the sound. The spectro-temporal density of sound may therefore be of particular relevance in cortical processing. Our findings suggest that low stimulus rates may produce a specific acoustic environment that shapes the primary auditory cortex through very different processing than for spectro-temporally more dense and complex sounds.

The role of sound in adult and developmental auditory cortical plasticity.

The purpose of the current review is to highlight the role of the acoustic environment in auditory cortical plasticity. In order do this we have reviewed our past studies on auditory cortical plasticity based on long-latency evoked potential recordings in humans following cochlear implantation, and multiple single-unit recordings from cat auditory cortex following noise trauma and exposure to a non-deafening acoustic environment. The results of these studies, and those of other investigators highlighted here, show that the auditory cortex shows plastic changes throughout life. Those that occur during maturation are typically considered the most profound and long lasting. In that case plasticity is beneficial as it allows adaptation to behaviorally important sound and adapts easily to changes induced by deafness and subsequent application of hearing aids or cochlear implants. In children as well as adults, changes in cortical representation of frequency can occur following hearing loss, but may be accompanied by unpleasant side effects such as tinnitus. Long exposure to a spectrally enhanced acoustic environment of moderate sound level that does not cause hearing loss paradoxically also results in pronounced changes in the cortical tonotopic maps. These changes are very similar to those following noise trauma. This review provides evidence that in adults, long-lasting plastic changes in auditory cortex occur even in the absence of behaviorally relevant acoustic stimulation. However, in children, the long lasting absence of auditory stimulation arrests cortical development.

Role of auditory cortex in noise- and drug-induced tinnitus.

PURPOSE: To elucidate the role of auditory cortex in tinnitus. METHOD: Neurophysiological findings in cat auditory cortex following noise trauma or the application of salicylate and quinine, all expected to induce tinnitus, were reviewed. Those findings were interpreted in the context of what is expected from studies in humans, specifically in the brains of people with tinnitus. RESULTS: Tinnitus is an auditory percept to which several central structures in the auditory system may contribute. Because the central auditory system has both feed-forward connections and feedback connections, it can be described as a set of nested loops. Once these loops become activated in a pathological fashion, as they may be in tinnitus, it becomes hard to assign importance to each contributing structure. Strongly interconnected networks, that is, neural assemblies, may be determining the quality of the tinnitus percept. CONCLUSION: It is unlikely that tinnitus is the expression of a set of independently firing neurons, and more likely that it is the result of a pathologically increased synchrony between sets of neurons. There is clear evidence for this from both evoked potentials and from neuron-pair synchrony measures.