Cochlear synaptopathy: A Reconnection of Cochlear Neurons

Hearing loss and deafness are serious health problems that affect millions of individuals worldwide. More than 1.5 billion individuals lose hearing ability throughout their lives, with at least 430 million requiring treatment. According to the World Health Organization (WHO), more than one billion young people, sometimes unknowingly, put themselves at risk of irreversible hearing loss by listening to music at high volumes for lengthy periods of time. According to current data, more than 42 percent of people with any degree of hearing loss are over the age of 60. The prevalence of hearing loss (moderate or severe) increases exponentially with age, ranging from 15.4 percent in their 60s to 58.2 percent in those over 90, with a regional prevalence of 10.9–17.6 percent among those aged 60–69 years, 41.9–51.2 percent among those aged 80–89 years, and 52.9–64.9 percent among those aged above 90 years. Hearing reports from around the world Hearing loss happens when a person’s hearing capacity is reduced to the point where they are unable to hear as well as someone with normal hearing. Hearing thresholds of 20 decibels or above in both ears are regarded as “normal.” Those with a hearing threshold greater than 20 dB may be categorized as “hard of hearing” or “deaf” depending on the severity of their hearing loss.

For decades, the scientific and medical community agreed that the outer hair cells of the cochlea were the most sensitive to damage from aging, noise exposure, ototoxic medicines, and a number of other factors affecting the inner ear. Scientific studies in animals and humans indicated that the loss of outer hair cells always preceded the loss of auditory nerve fibers (Johnsson, 1974; Johnsson and Hawkins, 1976), and that cochlear neuron degeneration was a delayed result of sensory cell loss (Johnsson, 1974; Johnsson and Hawkins, 1976). Even now, transient elevations in hearing thresholds are seen as benign as a result of this idea. Due to the serious implications of hearing loss, several efforts have been undertaken to prevent and even fix it. Hearing professionals originally thought that aging and noise exposure affected just one kind of sensory cell: hair cells. Recent scientific studies, on the other hand, have found a new cause: cochlear synaptopathy. Cochlear synaptopathy refers to the loss of nerve cells that are connected to hair cells. The nerve cells that transmit nerve impulses from hair cells to the brain are affected by cochlear synaptopathy. This disorder was once known as “hidden hearing loss,” a descriptive adjective given the disorder’s evident consequences. Cochlear synaptopathy or cochlear nerve degeneration are more accurate terms. Cochlear synaptopathy is a precursor to aging-related hearing loss and noise-induced hearing loss.

Pure Tone Audiometry and other conventional hearing tests are insufficient for detecting cochlear synaptopathy. When the volume of a conversation reaches a certain level, the cells afflicted by cochlear synaptopathy become visible. Tonal audiometry, on the other hand, measures the lowest levels of sound conceivable. Other tests examine the electrical activity of the auditory system. These tests, among other things, are used to evaluate hearing thresholds in infants. These methods for assessing nerve cell loss in cochlear synaptopathy are currently inadequately accurate.

As a result, scientists are developing new and innovative methods to evaluate and understand among persons who have previously experienced hearing loss. Despite the fact that no measurement techniques are currently available, it is important to note that researchers from all over the world are actively researching the subject. Synaptopathy is a synaptic connection disorder. Neuronal loss is referred to as cochlear loss. As a result, we’ll need to perform auditory nerve measures. In contrast to subjective audiometry, which is based on psycho-acoustic techniques, objective audiometry refers to any procedures that quantify physiological interactions after hearing and are related to hearing. In reaction to acoustic stimuli, the physical properties of the tympanic membrane (impedance audiometry), oto-acoustic emissions (OAE), and electric processes occurring in the hearing nerve, hearing pathways, and brain (auditory evoked potentials) may all be measured. Sound waves that go from the inner ear to the external meatus via the ossicles and eardrum are referred to as otoacoustic emissions (OAE). OAEs are the product of non-linear and active cochlear sound pre-processing processes that occur in the micro-mechanics of the basilar membrane and are responsible for the ear’s high sensitivity, wide dynamic range, and capacity to distinguish between frequencies. The tiny motions of the outer hair cells are the cause of cochlear emissions (OHC). Auditory evoked potentials (AEP), also known as auditory brainstem responses (ABR), are physiologically induced electric voltages that can be measured using electrodes and triggered by sound stimuli, providing differential diagnostic insights, particularly for distinguishing sensory and neural hearing problems.

Furthermore, efficient synaptic transmission at the ribbon synapse of auditory hair cells is required for hearing. The synapse is distinguished by the presence of a massive presynaptic organelle, the synaptic ribbon or dense body, which chains synaptic vesicles and is linked to the active zone. This synapse’s performance is exceptional in a variety of ways. Ribbon synapses allow neurons to transfer light impulses with several orders of magnitude of dynamic range. This is performed by encoding intensity fluctuations in the tonic rate of transmitter release, requiring the release of hundreds to thousands of synaptic vesicles per second. (Nouvian and al., 2006)

The purpose of this study is to address fundamental concerns concerning the identification and treatment of synaptic dysfunction in hair cells. The development of new test methods must conduct a thorough examination of studies measuring cochlear synaptopathy in people and animal models. What audiologic measures have been used to assess cochlear synaptopathy in both human and animal models, and if there is enough evidence to prescribe specific clinical tests for cochlear synaptopathy detection. Following that, we’ll try to discuss the perceptual implications of cochlear synaptopathy, how we can quantify it at this point, and what we would expect from such a discovery in terms of a variety of auditory diseases.

Study Design

This thesis followed a literature review study design and methodology to collect data. The study identified and evaluated different literature covering cochlear synaptopathy research on how to diagnose and treat it.

Search Strategy

First, relevant databases with important information on cochlear synaptopathy were selected. As potential sources of study materials and information, PubMed, The Journal of Neuroscience, Seminars in Hearing, Current Biology, and Science Reports were chosen. Furthermore, the World Health Organization and Hearing Research were highlighted as prospective sources of key information.

These databases were chosen because they provide relevant information to cochlear synaptopathy diagnosis and potential therapy, and they were sufficient to allow this thesis to achieve its goals. Unique search terms and terminology were aimed at exploring relevant literature and articles. Key words including “cochlear synaptopathy,” “hidden hearing loss,” “theoretical diagnosis,” “future solutions,” and “synapses regeneration,” among others, were used to refine the search and find the most precise literature.

The chronology literature search focused on experimental studies of cochlear synaptopathy that included audiological measurements as diagnostic tools, treatment and were published in peer-reviewed journals. Articles with either animal or human participants were included. Eight articles were used in the chronological findings of the cochlear synaptopathy diagnosis and four articles for the treatment. The findings of diagnostic approaches for therapy identified in the evaluated research, such as Distortion product otoacoustic emissions (DOAEs), auditory brainstem response (ABR), envelop following response (EFR), and others, were searched.

Standard audiometric testing is insufficient for diagnosing cochlear synaptopathy. Patients with any of these diseases frequently complain about difficulty understanding speech in noise, as well as other issues such as tinnitus. Previous studies, on the other hand, discovered significant loss of cochlear afferent synapses and progressive cochlear nerve degeneration in noise-exposed ears with maintained thresholds and no hair cell loss. (Kujawa and Liberman 2009).

Sergeyenko et al. (2013) studied age-related cochlear synaptic and neuronal degeneration in CBA/CaJ mice that had never been exposed to high-level noise. Cochlear hair cell and neuronal function were measured using distortion product otoacoustic emissions and auditory brainstem responses, respectively.  Hair cells, cochlear neurons, and synaptic components such as presynaptic ribbons and postsynaptic glutamate receptors were quantified using confocal and conventional light microscopy in immunostained cochlear whole mounts and plastic-embedded slices. Cochlear synaptic loss develops and is seen throughout the cochlea from development (4 weeks) through old age (144 weeks), far before age-related changes in thresholds or hair cell counts. Cochlear nerve degeneration reflects synaptic loss over time. The results show that the brain response provides important functional clues to synaptopathy; these may be collected noninvasively, enhancing the chances of translation to human clinical characterization.

However, because cochlear synaptopathy can develop without any quantifiable changes in audiometric thresholds, it can go undetected by traditional clinical diagnoses. Sensitive and precise non-invasive assessments at the individual patient level must be established to understand the perceptual consequences of synaptopathy and to evaluate the efficacy of developing therapeutics.

Using analogous tests in people and animals, Mehraei et al. (2016) observed in that the impact of masking noise on the latency of the more robust ABR wave-V paralleled changes in ABR wave-I amplitude. Furthermore, in our human sample, the effect of noise on wave-V delay predicts perceptual temporal sensitivity. They discovered that variations in ABR wave-V delay caused by noise may be used to diagnose cochlear synaptopathy in humans. Such noise exposure destroys synaptic connections between cochlear hair cells and auditory nerve fibers. There is no clinical test for this synaptopathy in humans. In animals, synaptopathy reduces the amplitude of auditory brainstem response (ABR) wave-I. Unfortunately, ABR wave-I is difficult to measure in humans, limiting its clinical use. Although there are concerns that cochlear synaptopathy affects people with normal hearing thresholds, no clinical test that is a reliable marker of such loss has been described. They show that the delay of auditory brainstem response wave-V in noise correlates with auditory nerve loss by integrating human and animal data. This is the first research on normal hearing threshold human listeners to relate individual variations in behavior and auditory brainstem response time to cochlear synaptopathy. These findings can be used to design a clinical test to detect this previously unknown kind of noise-induced hearing loss in people.

Liberman et al. (2016) recruited college students and divided them into low-risk and high-risk groups based on self-report of noise exposure and use of hearing protection in order to look for signs of cochlear synaptopathy in humans. Cochlear function was assessed using otoacoustic emissions and click-evoked electrocochleography, whereas hearing was assessed using behavioral audiometry and word recognition with or without noise, as well as temporal compression and reverberation. Both groups exhibited normal thresholds at standard audiometric frequencies, but the high-risk group had significant threshold elevation at high frequencies (10–16 kHz), which is consistent with noise damage in its early phases.

Electrocochleography indicated a significant difference in the ratio of waveform peaks produced by hair cells (Summating Potential; SP) vs. cochlear neurons (Action Potential; AP), i.e., the SP/AP ratio, indicating selective neuronal loss. In addition, the high-risk group performed significantly poorer on word recognition in noise or with temporal compression and reverberation, and they reported hyperacusis-like reactions to sound. These findings suggest that the SP/AP ratio may be useful in the diagnosis of cochlear synaptopathy and that noise-induced loss of cochlear nerve synapses leads to deficits in hearing abilities in difficult listening situations even when normal thresholds at standard audiometric frequencies are present, as suggested by animal models.

Barbee et al. (2018) showed that Cochlear Synaptopathy was assessed using pure-tone audiometry to 20 kHz, otoacoustic emissions, electrocochleography, auditory brainstem response (ABR), electrophysiological tests, speech recognition in noise with and without temporal distortion, interviews, and self-report measures. They conclude that ultra-high-frequency audiometry may help in the identification of individuals with sensory hair cell loss that is not obvious on standard audiograms in the case of “hidden hearing loss.” ABR wave I amplitude, the summating potential-to-action potential ratio, and speech recognition in noise with and without temporal distortion were all promising nonbehavioral indicators for Cochlear Synaptopathy. Self-report questionnaires may also aid in the identification of auditory impairment in people with normal hearing.

Bharadwaj et al. (2019) explored six external variables through a network of connected human studies to better understand their effects. They show that these suprathreshold physiological assays have across-individual correlations with each other, indicating contributions from a common physiological source consistent with cochlear synaptopathy, and they discuss the application of these assays to two key outstanding questions, as well as some remaining barriers, using strategies that may help mitigate the effects of such extraneous factors. They took into account suprathreshold ABR wave I amplitudes and I/V amplitude ratios, as well as envelope following responses EFR “slopes” and the middle ear muscle reflex MEMR. According to them, the MEMR was the most promising choice for a diagnostic measure of synaptopathy.

Monahgan et al. (2020) investigated the neuronal representation of speech in the auditory midbrain of gerbils with “hidden hearing loss” using noise that only temporarily elevated hearing thresholds. They discovered that noise-exposed rats’ brain reactions to speech stimuli were significantly amplified, with a more dramatic increase at moderate sound levels than at high sound intensities. They demonstrated that a specific combination of peripheral damage and central compensation could explain listening difficulties despite normal hearing thresholds. Cochlear synaptopathy is also connected to middle ear muscle (MEM) reflex strength measures in mice, likely because missing high-threshold neurons are important generators of this reflex.

Mepani et al. (2020) hypothesized that measurements of the MEM reflex would be superior than other peripheral function tests in predicting hearing problems in challenging listening situations in human participants. Results suggest that, among normal-hearing subjects, there is a significant peripheral contribution to diminished hearing performance in difficult listening environments that is not captured by either threshold audiometry or DPOAEs. The significant univariate correlations between word scores and either SP/AP, SP, MEM reflex thresholds, or AP amplitudes (in that order) are consistent with a type of primary neural degeneration. However, interpretation is clouded by uncertainty as to the mix of pre- and postsynaptic contributions to the click-evoked SP.  Because noise-induced neuropathy preferentially targets neurons with high thresholds and low spontaneous rate, and phase locking to temporal envelopes is especially strong in these fibers, measuring envelope following responses (EFRs) may be a more robust marker of cochlear synaptopathy.

Mepani et al. (2021) examined connections between EFR envelope following responses magnitudes and rectangular vs. sinusoidal modulation by measuring performance scores on a range of challenging word-recognition tasks among listeners with normal audiograms. Higher harmonics of EFR magnitudes induced by a rectangular-envelope stimulus were strongly associated with word scores, but not with sinusoidally modulated tones. These findings confirm that individual variations in synaptopathy may be a source of speech recognition variability even when normal thresholds at standard audiometric frequencies are present. The resultant correlations with word recognition performance are consistent with a contribution of cochlear neural damage to deficits in hearing in noise abilities.

• Chronology Evolution of diagnosis test of cochlear synaptopathy
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Exposures that generate only reversible threshold changes (and no hair cell loss) in noise-induced hearing loss cause irreversible loss of more than 50% of cochlear-nerve/hair-cell synapses. Similarly, in age-related hearing loss, cochlear synapses’ degeneration precedes both hair cell loss and threshold rise. This primary neural degeneration has remained hidden for three reasons: First, the spiral ganglion cells, the cochlear neural elements commonly assessed in studies of sensorineural hearing loss, survive for years despite loss of synaptic connection with hair cells; second, the synaptic terminals of cochlear nerve fibers are unmyelinated and difficult to see in a light microscope; and third the degeneration is selective for cochlear-nerve fibers with high thresholds.  A recent study on mice and guinea pigs has called that notion into question. Kujawa et al. (2015) propose that: primary neuronal degeneration contributes significantly to the perceptual handicap in sensorineural hearing loss. And in cases where the hair cells survive, neurotrophin therapies can elicit neurite outgrowth from spiral ganglion neurons and re-establishment of their peripheral synapses. Therefore, treatments may be on the horizon.

Hill et al. (2016) investigated the pathomechanisms of sensory hair cell loss and proposed a potential target for protective intervention. Cellular viability is dependent on the maintenance of energy balance, which is primarily mediated by AMP (adenosine monophosphate-activated protein) activated protein kinase (AMPK). Noise exposure raised the levels of phosphorylated AMPK in hair cells in a noise intensity-dependent way in CBA/J mice. Noise-induced loss of outer hair cells (OHCs) and synaptic ribbons was reduced and auditory function was retained when AMPK was inhibited using siRNA or the pharmacological inhibitor compound C. Noise also enhanced the activity of the downstream AMPK kinase, liver kinase B1 (LKB1) in cochlear tissues. LKB1 siRNA suppression decreased noise-induced AMPK phosphorylation in OHCs, reduced loss of inner hair cell synaptic ribbons and OHCs, and protected against Noise-Induced Hearing Loss (NIHL). Noise exposure causes hair cell death and synaptopathy by activating AMPK via LKB1-mediated pathways, according to these findings.

By focusing on these pathways, there is a possibility of finding a new approach to prevent NIHL. For the first time, the scientists found that AMP-activated protein kinase (AMPK) activation in sensory hair cells is noise intensity dependent and contributes to noise-induced hearing loss via mediating the loss of inner and outer hair cell synaptic ribbons. Noise triggers AMPK1 phosphorylation by liver kinase B1 (LKB1), which is activated by intracellular ATP fluctuations. By suppressing AMPK or LKB1, or using the pharmacological inhibitor compound C, researchers were able to minimize outer hair cell and synaptic ribbon loss, as well as noise-induced hearing loss. They reveal fresh insights into the processes of noise-induced hearing loss and propose innovative strategies to prevent sensory hair cell death and cochlear synaptopathy.

Panganiban et al. (2018) demonstrated that noise exposure delivered to both sexed mice rapidly alter myelinating glial cells, resulting in molecular and cellular effects that precede nerve degeneration. Demyelination, inflammation, and broad expression alterations in myelin-related genes, including the RNA (Ribonucleic acid) splicing regulator Quaking (QKI) and many QKI target genes, define this reaction. QKI defective mice were studied, and it was shown that QKI production in cochlear glial cells is required for appropriate myelination of spiral ganglion neurons and Auditory Nerve (AN) fibers, as well as adequate hearing. Their findings suggest that QKI dysregulation is an important early component in noise response, altering cochlear glia function and eventually leading to auditory nerve demyelination and hearing loss. Myelinating glia ensheathe most AN fibers and spiral ganglion neurons, providing insulation and ensuring speedy passage of nerve impulses from the cochlea to the brain. They state that auditory glia cells ensheath a majority of spiral ganglion neurons with myelin, protect auditory neurons, and allow for fast conduction of electrical impulses along the auditory nerve. They show that noise exposure causes glial dysfunction leading to myelin abnormality and altered expression of numerous genes in the auditory nerve, including QKI, a gene implicated in regulating myelination. A conditional mouse model that solely reduced QKI in glia revealed that QKI depletion alone was enough to cause myelin-related abnormalities and auditory functional deficits. These findings identify QKI as a critical molecular target in noise response and a causal factor in hearing loss. Histopathology has proven noise-induced and age-related loss of synaptic connections between auditory nerve fibers and cochlear hair cells in various mammalian species. Nevertheless, its prevalence in humans, as deduced from electrophysiological tests, remains contentious.

Nevoux et al. (2021) show here that the repulsive axonal guidance molecule a RGMa (Repulsive Guidance Molecule) acts to prevent regrowth and synaptogenesis of peripheral auditory nerve fibers with inner hair cells. Siebold et al. (2017) demonstrated that the repulsive guidance molecule (RGM) plays a key role in many fundamental processes, including cell migration, differentiation, and apoptosis, both during and after organ development. Since then, four distinct versions of this soluble or membrane-bound molecule have been described in vertebrates: RGMa, RGMb (or DRAGON), RGMc (or hemojuvelin), and RGMd (only in fish) (Siebold et al, 2017; Demicheva et al 2015). RGMs play a key role in the nervous system (Matsunaga et al, 2004). Neogenin1 is a dependence receptor that, in the absence of RGM, can trigger cell death (Mehlen and Bredesen, 2004). In prior research, Nevoux et al. (2021) discovered that an antibody against RGMa boosted spiral ganglion neuron innervation of the postnatal organ of Corti. These experiments were carried out as an in vitro model for the replacement of auditory neurons by embryonic stem cells in an effort to develop stem cell-based treatments for auditory neuropathy, the loss of auditory neurons that occurs in genetic diseases, as well as age and noise-related cochlear insults. Glutamatergic synapses exist between inner hair cells and cochlear afferent neurons. Kainic acid (KA), a glutamate analog, depolarizes neurons but can potentially be neurotoxic (Coyle, 1983). Pujol et al. (1985) described significant swelling of auditory dendrites in the Corti organ following a local injection of 1 nmol KA13. This finding agrees with earlier ultrastructural studies of KA neurotoxicity in different neural tissues. This is a type of auditory neuropathy in which the cell bodies of the neurons survive but the synapses are damaged, and new research shows that this type of damage occurs as the primary lesion in sensorineural hearing loss (Kujawa and Liberman ,2006; Wu et al., 2019).

Nevoux et al. (2021) investigated whether inhibiting RGMa would assist in the repair of these synapses in an in vitro model of kainate excitotoxicity as well as in vivo following noise-induced synapse destruction. The findings indicate that inhibiting RGMa is an effective therapy for synapse loss and may thus be a feasible way to treat individuals with this condition. The treatment of noise-exposed animals with an anti-RGMa inhibiting antibody resulted in the regeneration of inner hair cell synapses and the recovery of wave-I amplitude of the auditory brainstem response, indicating successful synaptopathy reversal.

• Chronology Evolution of treatment of cochlear synaptopathy
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Cochlear synaptopathy is a disorder that was found in 2009 in mice, subsequently in other animals studied, and finally in a human corpse in 2019. (Wu et al., 2019; Wu et al., 2021). Of course, researchers are concentrating on developing an indirect technique for defining synaptopathy using behavioral and electrophysiological testing. Furthermore, primary neuronal degeneration contributes significantly to the perceptual handicap in sensorineural hearing loss, and it may play a role in the development of tinnitus and other associated perceptual abnormalities (Hickox and Liberman, 2014; Knipper et al., 2013).

Recent studies suggest that millions of people may be at risk of permanent impairment from cochlear synaptopathy, the age-related and noise-induced degeneration of neural connections in the inner ear. Cochlear synaptopathy is defined as neuronal loss. As a result, we’ll need to measure the auditory nerve. It also results in issues with intelligibility, especially in the presence of noise. We need a difficult speech audiometry approach that is presented loudly and at a presentation level that saturates low-threshold fibers. These two critical components must be included in the diagnosis (Wu et al., 2019; Wu et al., 2021). Finally, we know that cochlear synaptopathy is associated with age and exposure to noise. If the measures are effective, we can anticipate them to differ considerably between older patients and/or those with a medical history of noise overexposure and young people who are more susceptible to the negative effects of noise. Using a battery of electrophysiological tests and psychophysics, Significant correlations between certain cochlear nerve measurements and speech audiometry scores when we presented to word subjects (NU-6) in difficult listening environments, such as the presence of white noise with a very low signal-to-noise ratio (Grant et al., 2020; Mepani et al., 2020; Mepani et al., 2021). More precisely, using electrocochleographic methods, they demonstrated that among patients with the lowest speech audiometry scores, the summation potential (SP) was high and the potential cochlear nerve (PA) activity was low (Grant et al.,2020; Liberman et al.,2016). It is important to highlight that gender and age differences could not explain these findings. Previous research has demonstrated that the stapedial reflex test is a more sensitive diagnostic of cochlear synaptopathy than the suprathinal amplitude of the PEAPs wave 1 in synaptopathic animals with normal hearing (Valero et al.,2016; Valero et al.,2018). They employed an approach inspired by Keefe and colleagues (Keefe et al., 2010) to assess changes in reflectance over a wide spectral range. Stapedial reflex thresholds were shown to be strongly associated with speech audiometry scores after adjusting for age and gender (Mepani et al.,2020).

Finally, a recent study included an electrophysiological evaluation of reactions following the signal envelope, often known as EFR (Envelope Following Responses), FFR (Frequency Following Responses), or even ASSR (Auditory Steady-State Responses), to the list of tests (Mepani et al.,2021). The idea behind these studies is that high threshold fibers, which are especially vulnerable to cochlear synaptopathy, are exceedingly sensitive to temporal fluctuations in the sound envelope. These reflexes should be considerably reduced at the synaptopathic level, as observed in people who struggled the most to repeat a list of sentences given in noise (Mepani et al.,2021). In the setting of cochlear synaptopathy, auditory peripheral models revealed a significant drop in EFRs (Encina-Llamas et al.,2019).

What is the significance of such a discovery?

The development of a clinical diagnosis of cochlear synaptopathy in humans is critical if we want to determine its prevalence in patients with hearing loss as well as those with normal audiograms, especially because excessive noise exposure in adolescents and young adults worsens the progression of this hearing loss (Fernandez et al.,2015; Wu et al.,2021). Early identification is crucial for identifying patients who may have had significant inner ear damage in the past, prior to their hearing thresholds being elevated. Early identification is also required for assessing the real risks caused by excessive sound exposure in order to develop recommendations and legislation for noise reduction and to raise public awareness of the dangers it poses. Acquiring objective measurements of cochlear synaptopathy and defining its evolution over time are two essential phases in selecting candidates for future therapies as well as assessing their efficacy. According to the current study, overexpression of the growth factor neurotrophin may cause synaptogenesis and regeneration of synapses between the auditory nerve and internal hair cells in mice (Wan et al.,2014).

Suzuki et al. (2016) discovered that prospective administration-based therapies such as neurotrophin in the round cochlear window (Salt et al., 2011) result in partial hearing recovery in animals. As a result, cochlear neuron reconnection appears to be on the horizon. Because spiral ganglion neurons survive for months (in animal models) and years (in humans) after the causal trauma, there may be a long therapeutic window for the treatment of synaptopathy. However, finding the best antibody dosage and manner of delivery would need more research. Further therapy development is thus required, which will include research to establish an appropriate dose following synaptopathic noise exposure, either as a single event or as a lifetime of minor doses. Moreover, if the discovery of cochlear synaptopathy has inspired such interest in the scientific and medical communities, the future possibility of therapies extends far beyond restoring hearing impaired intelligibility. Indeed, cochlear synaptopathy may play a role in the development of other sensorineural deafness-related perceptual disorders such as tinnitus and hyperacusis. Presbycusis and noise overexposure, two etiologies connected to cochlear synaptopathy in humans, are highly linked to tinnitus and increase the patient’s likelihood of developing it. With the discovery of cochlear synaptopathy, we now have a solid lead for attempting to comprehend the genesis of tinnitus, and therefore, for the first time, the possibility of going beyond conventional therapies, which consist of suppressing the sensation of tinnitus or learning to live with it. Indeed, if therapeutic medications like neurotrophin are successful in restoring nerve-hair cell synapses, we may expect one of the side effects of this treatment to be a reduction in central gain as a result of the restoration of peripheral information, and hence a reduction or eradication of tinnitus.

Cochlear synaptopathy is the loss of nerve endings in the cochlea while the cell bodies of primary auditory neurons remain intact. It is undetectable by complete audiometry, yet it has a major impact on noise perception and may be the cause of tinnitus.

A new research study has proven that it could be diagnosed by using objective audiometry. Real molecular and cellular therapies, such as viral gene transfer and genome “editing” approaches, are now being studied in animal models. Injecting an antibody aimed against a protein that slows neuronal growth through the round window allows nerve endings to repair and reconnect after sound injury. These findings have implications not just for treating synaptopathies induced by acoustic damage and/or cochlear aging, but also for the creation of implants. Furthermore “Smart” hearing aids will also include signal processing techniques to minimize noise and filters suited to each patient’s specific needs. Hearing aids can partially compensate for the loss of function of damaged cells due to advancements in sound processing technology. An example of a new approach to technology is the Deep Neural Network: which is a sort of machine learning that mirrors how the human brain learns.

What may we expect in the following years?

Our major objective is to improve the quality of life of people with hearing loss by giving them individualized follow-up in order to motivate them to understand their needs. Our approach has changed with the help of this new technology, and the outcomes with hearing aids have been really beneficial.