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.

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.

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.

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.

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.

Ups and Downs in 75 Years of Electrocochleography.

Before 1964, electrocochleography (ECochG) was a surgical procedure carried out in the operating theatre. Currently, the newest application is also an intra-operative one, often carried out in conjunction with cochlear implant surgery. Starting in 1967, the recording methods became either minimal- or not-invasive, i.e., trans-tympanic (TT) or extra tympanic (ET), and included extensive studies of the arguments pro and con. I will review several valuable applications of ECochG, from a historical point of view, but covering all 75 years if applicable. The main topics will be: (1) comparing human and animal cochlear electrophysiology; (2) the use in objective audiometry involving tone pip stimulation-currently mostly pre cochlear implantation but otherwise replaced by auditory brainstem response (ABR) recordings; (3) attempts to diagnose Ménière's disease and the role of the summating potential (SP); (4) early use in diagnosing vestibular schwannomas-now taken over by ABR screening and MRI confirmation; (5) relating human electrophysiology to the effects of genes as in auditory neuropathy; and (6) intracochlear recording using the cochlear implant electrodes. The last two applications are the most recently added ones. The "historical aspects" of this review article will highlight the founding years prior to 1980 when relevant. A survey of articles on Pubmed shows several ups and downs in the clinical interest as reflected in the publication counts over the last 75 years.

Acquired hearing loss and brain plasticity.

Acquired hearing loss results in an imbalance of the cochlear output across frequency. Central auditory system homeostatic processes responding to this result in frequency specific gain changes consequent to the emerging imbalance between excitation and inhibition. Several consequences thereof are increased spontaneous firing rates, increased neural synchrony, and (in adults) potentially restricted to the auditory thalamus and cortex a reorganization of tonotopic areas. It does not seem to matter much whether the hearing loss is acquired neonatally or in adulthood. In humans, no clear evidence of tonotopic map changes with hearing loss has so far been provided, but frequency specific gain changes are well documented. Unilateral hearing loss in addition makes brain activity across hemispheres more symmetrical and more synchronous. Molecular studies indicate that in the brainstem, after 2-5 days post trauma, the glutamatergic activity is reduced, whereas glycinergic and GABAergic activity is largely unchanged. At 2 months post trauma, excitatory activity remains decreased but the inhibitory one is significantly increased. In contrast protein assays related to inhibitory transmission are all decreased or unchanged in the brainstem, midbrain and auditory cortex. Comparison of neurophysiological data with the molecular findings during a time-line of changes following noise trauma suggests that increases in spontaneous firing rates are related to decreases in inhibition, and not to increases in excitation. Because noise-induced hearing loss in cats resulted in a loss of cortical temporal processing capabilities, this may also underlie speech understanding in humans.

Effects of long-term non-traumatic noise exposure on the adult central auditory system. Hearing problems without hearing loss.

It is known that hearing loss induces plastic changes in the brain, causing loudness recruitment and hyperacusis, increased spontaneous firing rates and neural synchrony, reorganizations of the cortical tonotopic maps, and tinnitus. Much less in known about the central effects of exposure to sounds that cause a temporary hearing loss, affect the ribbon synapses in the inner hair cells, and cause a loss of high-threshold auditory nerve fibers. In contrast there is a wealth of information about central effects of long-duration sound exposures at levels ≤80 dB SPL that do not even cause a temporary hearing loss. The central effects for these moderate level exposures described in this review include changes in central gain, increased spontaneous firing rates and neural synchrony, and reorganization of the cortical tonotopic map. A putative mechanism is outlined, and the effect of the acoustic environment during the recovery process is illustrated. Parallels are drawn with hearing problems in humans with long-duration exposures to occupational noise but with clinical normal hearing.

Can Animal Models Contribute to Understanding Tinnitus Heterogeneity in Humans?

The brain activity of humans with tinnitus of various etiologies is typically studied with electro- and magneto-encephalography and functional magnetic resonance imaging-based imaging techniques. Consequently, they measure population responses and mostly from the neocortex. The latter also underlies changes in neural networks that may be attributed to tinnitus. However, factors not strictly related to tinnitus such as hearing loss and hyperacusis, as well as other co-occurring disorders play a prominent role in these changes. Different types of tinnitus can often not be resolved with these brain-imaging techniques. In animal models of putative behavioral signs of tinnitus, neural activity ranging from auditory nerve to auditory cortex, is studied largely by single unit recordings, augmented by local field potentials (LFPs), and the neural correlates of tinnitus are mainly based on spontaneous neural activity, such as spontaneous firing rates and pair-wise spontaneous spike-firing correlations. Neural correlates of hyperacusis rely on measurement of stimulus-evoked activity and are measured as increased driven firing rates and LFP amplitudes. Connectivity studies would rely on correlated neural activity between pairs of neurons or LFP amplitudes, but are only recently explored. In animal models of tinnitus, only two etiologies are extensively studied; tinnitus evoked by salicylate application and by noise exposure. It appears that they have quite different neural biomarkers. The unanswered question then is: does this different etiology also result in different tinnitus?

Somatic memory and gain increase as preconditions for tinnitus: Insights from congenital deafness.

Tinnitus is the conscious perception of sound heard in the absence of physical sound sources internal or external to the body. The characterization of tinnitus by its spectrum reflects the missing frequencies originally represented in the hearing loss, i.e., partially or completely deafferented, region. The tinnitus percept, despite a total hearing loss, may thus be dependent on the persisting existence of a somatic memory for the "lost" frequencies. Somatic memory in this context is the reference for phantom sensations attributed to missing sensory surfaces or parts thereof. This raises the question whether tinnitus can exist in congenital deafness, were somatic representations have not been formed. We review the development of tonotopic maps in altricial and precocial animals evidence for a lack of tinnitus in congenital deafness and the effects of cochlear implants on the formation of tonotopic maps in the congenitally deaf. The latter relates to the emergence of tinnitus in these subjects. The reviewed material is consistent with the hypothesis that tinnitus requires an established and actively used somatotopic map that leads to a corresponding somatic memory. The absence of such experience explains the absence of tinnitus in congenital bilateral and unilateral deafness.

Animal models of spontaneous activity in the healthy and impaired auditory system.

Spontaneous neural activity in the auditory nerve fibers and in auditory cortex in healthy animals is discussed with respect to the question: Is spontaneous activity noise or information carrier? The studies reviewed suggest strongly that spontaneous activity is a carrier of information. Subsequently, I review the numerous findings in the impaired auditory system, particularly with reference to noise trauma and tinnitus. Here the common assumption is that tinnitus reflects increased noise in the auditory system that among others affects temporal processing and interferes with the gap-startle reflex, which is frequently used as a behavioral assay for tinnitus. It is, however, more likely that the increased spontaneous activity in tinnitus, firing rate as well as neural synchrony, carries information that shapes the activity of downstream structures, including non-auditory ones, and leading to the tinnitus percept. The main drivers of that process are bursting and synchronous firing, which facilitates transfer of activity across synapses, and allows formation of auditory objects, such as tinnitus.

Maladaptive neural synchrony in tinnitus: origin and restoration.

Tinnitus is the conscious perception of sound heard in the absence of physical sound sources external or internal to the body, reflected in aberrant neural synchrony of spontaneous or resting-state brain activity. Neural synchrony is generated by the nearly simultaneous firing of individual neurons, of the synchronization of membrane-potential changes in local neural groups as reflected in the local field potentials, resulting in the presence of oscillatory brain waves in the EEG. Noise-induced hearing loss, often resulting in tinnitus, causes a reorganization of the tonotopic map in auditory cortex and increased spontaneous firing rates and neural synchrony. Spontaneous brain rhythms rely on neural synchrony. Abnormal neural synchrony in tinnitus appears to be confined to specific frequency bands of brain rhythms. Increases in delta-band activity are generated by deafferented/deprived neuronal networks resulting from hearing loss. Coordinated reset (CR) stimulation was developed in order to specifically counteract such abnormal neuronal synchrony by desynchronization. The goal of acoustic CR neuromodulation is to desynchronize tinnitus-related abnormal delta-band oscillations. CR neuromodulation does not require permanent stimulus delivery in order to achieve long-lasting desynchronization or even a full-blown anti-kindling but may have cumulative effects, i.e., the effect of different CR epochs separated by pauses may accumulate. Unlike other approaches, acoustic CR neuromodulation does not intend to reduce tinnitus-related neuronal activity by employing lateral inhibition. The potential efficacy of acoustic CR modulation was shown in a clinical proof of concept trial, where effects achieved in 12 weeks of treatment delivered 4-6 h/day persisted through a preplanned 4-week therapy pause and showed sustained long-term effects after 10 months of therapy, leading to 75% responders.

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.

Tinnitus and neural plasticity (Tonndorf lecture at XIth International Tinnitus Seminar, Berlin, 2014).

Ten years ago, animal models of noise-induced hearing loss predicted three cortical neural correlates of tinnitus resulting from noise-induced hearing loss: increased spontaneous firing rates, increased neural synchrony, and reorganization of tonotopic maps. Salicylate also induces tinnitus, however, the cortical correlates were reduced spontaneous firing rates, unchanged neural synchrony but some change to the tonotopic map. In both conditions increased central gain, potentially a correlate of hyperacusis, was found. Behavioral animal models suggested that tinnitus occurred, albeit not in all cases. The study of the neural substrates of tinnitus in humans is currently strongly based on network connectivity using either spontaneous EEG or MEG. Brain imaging combined with powerful analyses is now able to provide in excellent detail the lay out of tonotopic maps, and has shown that in people with tinnitus (and clinical normal hearing up to 8 kHz) no changes in tonotopic maps need to occur, dispensing therefore of one of the postulated neural correlates. Patients with hyperacusis and tinnitus showed increased gain, as measured using fMRI, from brainstem to cortex, whereas patients with tinnitus without hyperacusis only showed this in auditory cortex. This suggested that top down mechanisms are also needed. The open problems can be formulated by the following questions. 1) Are the neural substrates of tinnitus etiology dependent? 2) Can animal results based on single unit and local field potentials be validated in humans? 3) Can sufficient vs. necessary neural substrates for tinnitus be established. 4) What is the role of attention and stress in engraining tinnitus in memory?

Animal models of auditory temporal processing.

Human temporal processing relies on bottom-up as well as top-down mechanisms. Animal models thereof, in the vast majority, are only probing the bottom-up mechanisms. I will review the vast literature underlying auditory temporal processing to elucidate some basic mechanisms that underlie the majority of temporal processing findings. Some basic findings in auditory temporal processing can all be based on mechanisms determining perstimulatory adaptation of firing rate. This is based on transmitter release mechanisms in peripheral as well as central synapses. It is surprising that the adaptation and recovery time constants that define perstimulatory firing rate adaptation are not very different between auditory periphery and auditory cortex when probed with similar stimuli. It is shown that forward masking, gap and VOT detection, and temporal modulation transfer functions are all directly related to perstimulatory adaptation, whereas stimulus-specific adaptation is at least partly dependent on it. Species differences and the fact that most of the studies reviewed were done in anesthetized animals need to be taken into account when extrapolating animal findings to human perceptual studies. In addition, the accuracy of first-spike latency plays a major role in sound localization and in the brainstem mechanisms for periodicity pitch and forms the basis for understanding evoked potential studies in humans. These mechanisms are also crucial for determining neural synchrony underlying perceptual binding and some important aspects of stream segregation.

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.

Cross-correlations between three units in cat primary auditory cortex.

Here we use a modification of the Joint-Peri-Stimulus-Time histogram (JPSTH) to investigate triple correlations between cat auditory cortex neurons. The modified procedure allowed the decomposition of the xy-pair correlation into a part that is due to the correlation of the x and y units with the trigger unit, and a remaining 'pair correlation'. We analyzed 16 sets of 15-minute duration stationary spontaneous recordings in primary auditory cortex (AI) with between 11 and 14 electrodes from 2 arrays of 8 electrodes each that provided spontaneous firing rates above 0.22 sp/s and for which reliable frequency-tuning curves could be obtained and the characteristic frequency (CF) was estimated. Thus we evaluated 11,282 conditional cross-correlation functions. The predictor for the conditional cross-correlation, calculated on the assumption that the trigger unit had no effect on the xy-pair correlation but using the same fraction of xy spikes, was equal to the conventional pair-wise correlation function between units xy. The conditional correlation of the xy-pair due to correlation of the x and/or y unit with the trigger unit decreased with the geometric mean distance of the xy pair to the trigger unit, but was independent of the pair cross-correlation coefficient. The conditional pair correlation coefficient was estimated at 78% of the measured pair correlation coefficient. Assuming a geometric decreasing effect of activities of units on other electrodes on the conditional correlation, we estimated the potential contribution of a large number of contributing units on the measured pair correlation at 35-50 of that correlation. This suggests that conventionally measured pair correlations in auditory cortex under ketamine anesthesia overestimate the 'true pair correlation', likely resulting from massive common input, by potentially up to a factor 2.

Role of attention in the generation and modulation of tinnitus.

Neural mechanisms that detect changes in the auditory environment appear to rely on processes that predict sensory state. Here we propose that in tinnitus there is a disparity between what the brain predicts it should be hearing (this prediction based on aberrant neural activity occurring in cortical frequency regions affected by hearing loss and underlying the tinnitus percept) and the acoustic information that is delivered to the brain by the damaged cochlea. The disparity between the predicted and delivered inputs activates a system for auditory attention that facilitates through subcortical neuromodulatory systems neuroplastic changes that contribute to the generation of tinnitus. We review behavioral and functional brain imaging evidence for persisting auditory attention in tinnitus and present a qualitative model for how attention operates in normal hearing and may be triggered in tinnitus accompanied by hearing loss. The viewpoint has implications for the role of cochlear pathology in tinnitus, for neural plasticity and the contribution of forebrain neuromodulatory systems in tinnitus, and for tinnitus management and treatment.