Cochlear implantation can restore access to sound and speech understanding in subjects with substantial hearing loss. The Health Utilities Index Mark III (HUI3) measures the impact of an intervention on the patient’s quality of life and is sensitive to changes in hearing. In the current study we used factor analysis to predict a clinically important gain in HUI3 scores in adult cochlear implant recipients.Data were collected in an observational study for 137 adult recipients from a single center who had at least 1-year HUI3 follow-up. Demographic and other baseline parameters were retrospectively analyzed for their association with a clinically important HUI3 scale gain, defined as at least 0.1 points. Data were also collected for the speech spatial qualities (SSQ) scale.Baseline telephone use and HUI3 hearing, speech and emotion attribute levels were significantly associated with clinically important gains in HUI3 scores. However, SSQ scores increased significantly with or without clinically important HUI3 gains.Those subjects who were unhappy or experienced difficulties communicating with strangers or in a group were twice as likely to obtain a clinically important gain in health utility compared to those who were happy or had less difficulty communicating. Subjects who were unable to use the telephone prior to cochlear implantation were one and a half times more likely to obtain a clinically important gain. The SSQ scale was more sensitive to hearing improvements due to cochlear implantation. An inability to use the telephone is an easy to assess biomarker for candidacy for cochlear implantation. The success of a healthcare intervention is often measured by its impact on the patient’s quality of life. This provides a tool for comparing the success of different treatments, regardless of the condition they are targeting . StandarThe HUI3 consists of 15 questions addressing eight individual health attributes: vision, hearing, speech, ambulation, dexterity, emotion, cognition and pain. Each health attribute has 5 or 6 levels and a weighted health utility score assigned to each level which varies by attribute. These scores are then combined to give a measure of the overall health utility . An incrIn South Africa approximately 83% of the population depends on public health and 17% on the private healthcare market financed by the medical industry. Funding is provided for CIs on an ad hoc basis from the public health sector through Tygerberg Hospital, with large waiting lists for adult candidates. In countries where access to CI is limited, establishing who will benefit most is one way of prioritizing treatment. For cochlear implantation, however, outcomes are difficult to predict from preoperative measures . An actuThere is little published work in this area. A few studies have identified the preoperative presence of comorbidities, dizziness or tinnitus and the duration of deafness and depression scores as factors that have a significant influence on the change in HUI3 scores resulting from implantation , 20–22.The aim of this study was to determine which baseline factors may significantly influence clinically important gains in HUI3 in a large sample. A retrospective analysis was performed on data collected from one South African clinic who took part in the Cochlear Implant Recipient Observational Study (IROS) . We consData were gathered via a voluntary online international observational registry for hearing implants initiated by Cochlear Ltd . Data were collected in accordance with the Declaration of Helsinki. Ethics approval was obtained from the Health Research Ethics Committee 1, Stellenbosch University (reference N15/02/015). Each subject provided their written informed consent for their data to be included in the registry.We extracted data for all adult unilateral CI recipients (> 17 years old) implanted at the Tygerberg Hospital, Stellenbosch University Cochlear Implant Unit, between 2012 and 2019. Baseline data were collected prior to activation of the processor after a decision to implant had been made. Follow-up data had been collected up to 3 years post-implantation in some cases. However, here we focus on the gain from baseline to 1-year post-activation. Self-assessments were completed by the recipient either online or on paper and then entered into the database by a representative of the clinic.The Health Utilities Index Mark 3 (HUI3), a generic measure of health utility gains, was the primary measure . Change Table Weighting scores for given levels of each health attribute are used to produce a HUI3 “total” or multi-attribute score combining all eight attributes. For most attributes at least two levels need to be gained to result in changes of ≥ 0.1 in the combined HUI3 multi-attribute scores. This is a property of the way the HUI3 was constructed. However, as shown in Table As a secondary outcome measure data were also collected for the speech spatial qualities (SSQ) scale . This ist tests were used to examine change over time from baseline to year 1 follow-up. p values less than 0.05 were considered significant. All analyses were conducted in R4 [Because interest was in those who gained at least the minimum clinically important difference (MCID) of 0.1 HUI3 multi-attribute score units, change in HUI3 multi-attribute score was dichotomized at this value with a 1 representing achievement of at least the MCID and 0 otherwise. Fisher’s exact test was used to determine the association between the dichotomized HUI3 multi-attribute change score and variables of interest. Table ed in R4 .p < 0.001), which was maintained at years 2 and 3  of subjects had no change in hearing attribute level, with by far most of those starting and finishing at level 3. Overall, 74 (54%) subjects fell above the dividing line for significant hearing attribute level increase and 63 (46%) below. Thus, the transitions in hearing attribute level contributed to 74 of the total 81/137 subjects with ≥ 0.1 overall HUI3 gain.A closer look at the individual changes in hearing attribute levels is available in Table In Table Subjects unable to use the telephone preoperatively were one-and-a-half times more likely to obtain ≥ 0.1 gain in HUI3 scores (odds ratio OR 1.47); those reporting difficulty to be understood by strangers or worse twice as likely (OR 2.27); and those reporting being unhappy or worse two-and-a-half times more likely (OR 2.53). There was no effect of age, sex or duration of deafness. To put these into context, subjects unable to hear with hearing aids or worse at baseline had twice as much chance to obtain clinically important HUI3 gain as those who reported better hearing at baseline.At baseline, subjects unable to hear were one-and-a-half times (OR 1.52) more likely not to use the telephone compared to those that did. Of participants who gained ≥ 0.1 in HUI3 score, 63% did not use the telephone at baseline, while among those who did not gain ≥ 0.1 in HUI3 score a significantly smaller proportion did not use the telephone at baseline. By visit 1, only 18/137 subjects were still not able to use the telephone, with eight of these in the ≥ 0.1 and ten in the < 0.1 gain groups.p < 0.001) and for those who did not .SSQ scores improved significantly from baseline to 1 year both for who obtained clinically important gains in HUI3 score  were also more likely not to use the telephone (OR 1.52). Thus, telephone use is an easy parameter to use for the screening of potential adult CI candidates presenting to the audiology clinic. Take up of implants in adults is poor with less than 10% of suitable candidates receiving implants in western countries . This isThe Fisher’s exact test showed that there was also a non-random association between a meaningful gain on the HUI3 and the hearing, speech and emotion single attributes. Not surprisingly, those subjects with poor baseline hearing were more likely to gain more than 0.1 points. This comes from changes in the hearing attribute scale where subjects move from the worst hearing levels to the better levels following implantation Tables . HoweverThose who reported that strangers were unable to understand them, or even poorer verbal communication, were twice as likely to have a clinically significant gain in health utility. Improved overall verbal communication due to better hearing and other rehabilitation following CI may have contributed to this effect.Most subjects in both groups reported being happy or somewhat happy prior to implantation. However, those who were unhappy prior to implant were twice as likely to show a meaningful gain in the HUI3, probably due to the implant and rehabilitation process improving their communication and thus emotional state. Significant hearing loss has long been associated with depression, and this is the one factor which has previously been identified as linked with change in HUI3 scores following implantation . HoweverIn keeping with the larger cohort from the IROS study reported by Lenarz et al., there was no significant association between age or duration of deafness and the HUI3 outcomes . Age sho® implant recipients. However, recipients who were more motivated may have been more likely to agree to participate, which may influence outcomes. Data for some subjects were also included in the prior publication by Lenarz et al. [This was an observational study, and enrolment bias may be present in the sample. Investigators were instructed to offer participation to all consecutively implanted adult and adolescent Nucleusz et al. . As selfAfter cochlear implantation there was a statistically significant group gain in HUI3 scores at 1 year which was maintained at years 2 and 3. Those who did not use the telephone at baseline were 1.5 times more likely to get a clinically important gain of ≥ 0.1 in HUI3 multi-attribute score from cochlear implantation. Those with lower hearing, speech or emotion HUI3 single-attribute levels prior to implantation were also more likely to obtain clinically important gains in HUI3 scores. There was no effect of age or duration of deafness. An incapacity to use the telephone may be a useful biomarker for cochlear implant candidacy prior to formal audiological evaluation.For those the subjects who obtained < 0.1-point gain in HUI3, this could often be attributed to a lack of change in the hearing attribute level. A large proportion of this comes from the structure of the HUI3 hearing scales where subjects remain at level 3, able to hear with a hearing aid. However, mean hearing performance measured by the SSQ still increased significantly for that group after CI. The HUI3 scale stands in good stead as a health-utility instrument to measure the benefits of cochlear implantation for those with severe handicap due to hearing impairment, but lacks sensitivity to changes in hearing performance compared with a disease-specific measure such as the speech, spatial qualities (SSQ) scale.


Understanding how, when, and for how long the adult central auditory system adapts to hearing loss and aging is an important topic that is currently studied across the globe. Central auditory plasticity can occur from very rapid adaptation to long-term changes, and varies depending on the history of the sensory input or the influence of attention, learning, and decision-making. Despite continuous efforts, it is still unknown whether central auditory plasticity to hearing loss represents homeostatic mechanisms or maladaptive changes that lead to tinnitus and hyperacusis. Studies in this Special Issue of “Central Auditory Plasticity” encompass research relevant to the advancement of our understanding of the neurobiology underlying structural, molecular, electrophysiological and behavioral adaptations to hearing loss and ageing.The study by Kurioka et al.  focused Aging-related structural, molecular and functional changes occur at every level of the central auditory system. One of the most common findings is a loss of synaptic inhibition with aging, which has been proposed to be the base of aging-related changes in auditory cognition, such as diminished speech perception in complex environments and the perception of tinnitus. Studies speculated that downregulation of synaptic inhibition is a consequence of peripheral deafferentation and, therefore, is a homeostatic mechanism to restore excitatory/inhibitory balance. The study by Wang and colleagues  shows thIn order to accurately localize sounds on the horizontal plane, the binaural hearing system relies on computing the interaural time and level differences from the incoming acoustic signal. Improving binaural hearing has become highly relevant in clinical settings due to the appreciation of deaf patients’ needs to communicate and function in realistic, complex auditory environments. The study by Thakkar and colleagues  aimed toPrepulse inhibition (PPI) implies plasticity of a reflex and is related to automatic or attentional processes, and might be considered a potential marker of short- and long-term plasticity. The PPI plays a key role in normal brain activity; however, little is known about the intimate physiology, circuitry, and neurochemistry of sensorimotor gating mechanisms. In Gómez-Nieto et al. , authors


Presbycusis, physiological age-related hearing loss, is a major health problem because it is the most common cause of hearing impairment, and its impact will grow in the coming years with the aging population. Besides auditory consequences, the literature recently found an association between hearing loss and cognitive decline over the last two decades, emphasizing the importance of the early detection of presbycusis. However, the current hearing tests are not sufficient to detect presbycusis in some cases. Furthermore, the underlying mechanisms of this association are still under discussion, calling for a new field of research on that topic. In that context, this study investigates for the first time the interaction between presbycusis, eye movement latency and Stroop scores for a normal aging population. Hearing abilities, eye movement latency and the Stroop Victoria test were measured for 69 elderly (mean 66.7 ± 8.4) and 30 young (mean 25.3 ± 2.7) participants. The results indicated a significant relationship between saccade latency and speech audiometry in the silence score, independently from age. These promising results suggest common attentional mechanisms between speech processing and saccade latency. The results are discussed regarding the relationship between hearing and cognition, and regarding the perspective of expanding new tools for presbycusis diagnosis.  Aging in the brain involves a loss of sensory processing, motor performance and cognitive function caused by a loss of synaptic contact .The physiological loss of hearing with age, presbycusis, is a well-known phenomenon. This is the most common cause of hearing impairment, and is caused by multiple intrinsic and extrinsic risk factors . The prevalence of hearing loss for the senior population varies depending on studies, as studies use different hearing variables, different cutoffs for the definition of hearing loss, and different demographic characteristics in their cohorts . A studyThe auditory consequences of presbycusis are a bilateral and symmetric increase of the hearing threshold (beginning with the high frequencies), a decrease of frequency resolution, and a loss of comprehension, especially in noisy environments ,5,6. HowThe detection of presbycusis is currently performed with three main hearing tests: pure-tone audiometry, and speech intelligibility in silence and in noise. However, these hearing tests could sometimes fail to detect subtle deficiencies of hearing capacities . Normal In that context, the present study focuses on two aspects concerning the association between hearing loss and cognitive decline. The first one concerns the need to understand the multisensory mechanisms underpinning the ways in which hearing loss and cognitive decline relate to each other. The second, more translational aspect, aims to provide new sensitive tools that can contribute to the detection of even mild hearing deterioration as early as possible in elderly patients.These problems will be treated by assessing the relationship between presbycusis and eye movement latency.Eye movements are an ideal tool to examine the perception and action mechanisms of the brain, such as cognition, motor control and memory . Indeed,The eye movement latency is the reaction time to initiate the eye movement to reach a target. In a more general way, the reaction time is related to executive cognitive function ,22,23. TThe relationship between eye movement and cognitive executive functions is rather restricted to studies on saccade latency. For instance, the saccades latency is longer for people with mild cognitive impairment than for healthy elderly people, and a significant correlation between saccade latency and the MMSE  has been reported . Others The fact that hearing and eye movement reaction times are both related to cognition suggests a potential relationship between them. This study aims to open up a new research avenue on the triple relationship between age-related hearing loss, saccade and vergence eye movement, and cognition. The results could bring new insights for (i) the objectification and the understanding of the association between hearing loss and cognitive decline, and (ii) the development of new clinical tools for the diagnosis of presbycusis.To do this, we will assess the interaction between three functions: presbycusis, saccade and vergence latency, and executive cognitive function. The cognitive test used here will be the Stroop test, a golden test to measure the selective attention and inhibition capacities , which aWe hypothesize that poorer hearing will be related to longer latencies, and perhaps to lower scores for cognitive executive functions.The results confirm a link between eye movement and hearing loss, and are of both theoretical and clinical interest.relai d’information des sciences cognitives, France) platform of the CNRS, or by contacting associations which were likely to have people of appropriate ages. Some of them were retired, while others were still working. All of the participants were autonomous, and came to the laboratory without assistance. We can consider this sample as an average elderly population. Group Y was composed of people working in the same building.The participants were divided into two groups: an elderly group (Group E) composed of 69 participants aged between 51 and 84 years , and a young group (Group Y) composed of 30 participants aged between 21 and 30 years . Group E was recruited by the RISC .Informed consent was obtained from all of the participants after the nature of the procedure had been explained.Rather than focusing on the elderly group, which became smaller than planned due to the COVID 19 pandemic, we sought to add a group of young participants, enabling us to evaluate aging relative to the performances of young people, as well as progressive aging within the elderly group itself.The study was conducted in accordance with the Declaration of Helsinki, and approved by Ethics Committee “Ile de France II” . An audiometrist assessed all of the hearing tests with an audiometer of the brand Interacoustics (model AD629) in a sound booth calibrated cabin. These tests were composed of pure-tone hearing threshold audiometry and two speech recognition tests, one in silence and one in noise. An otoscopic evaluation was first performed to detect any foreign body in the outer ear canal that could bias the audiometric results.Pure-tone hearing threshold audiometry  measures audibility, e.g., the minimum intensity required to detect a sound. It was realized with a headset (audiometric TDH-39P), with one ear tested at the time. The score extracted from the pure-tone hearing threshold audiometry is the best ear’s PTA (pure-tone average). The hearing thresholds in dB HL for pure-tones of 250, 500, 750, 1000, 2000, 3000 and 4000 Hz were determined with 5-dB steps. Then, the PTA was calculated by meaning all of these thresholds. We decided to keep the PTA of the better ear in order to follow the hearing loss definition of the world health organization (WHO) , which iThe speech audiometry in silence was realized with a loudspeaker situated at 1 m in front of the participant  [The speech audiometry in noise was realized with three loudspeakers  situated at 1 m from the participant B: one be French) . This noIn total, 62 participants of Group E  and 19 participants of Group Y  performed the hearing tests; note that the hearing tests were carried out in a different place than the eye movement tests, and many of the young participants were no longer available.The different oculomotor movements  were tested via the REMOBI device, as first described by Kapoula et al. .The REMOBI device is a visio-acoustic surface composed of 48 LEDs  embedded at 4 isovergence arcs. The device includes different sequences, lighting up the LEDs in different patterns. The participants sat in front of the REMOBI device, which was placed at eye level, and were instructed to fixate the activated LED as quickly and accurately as possible and maintain the fixation. The sequence chosen on the REMOBI device enables testing a specific kind of eye movement. Two sequences were used in this study: the saccade sequence, measuring the left and right saccades, and the vergence sequence, measuring divergence and convergence .The saccade sequence comprises 20 trials of right saccades and 20 trials of left saccades, randomly interleaved. During each trial, a central LED, situated at 70 cm in front of the participant (the same distance from his left and right eye), is switched on at a random time between 1200 and 1800 ms. Then, a lateral LED to the right or to the left is lit for 2000 ms, following an overlap paradigm, i.e., the central LED switches off 200 ms after the onset of the lateral LED. The lateral LED forms an angle of 20° with the central LED, calling for a left saccade or right saccade of 20°.The vergence sequence comprises 20 trials of divergence and 20 trials of convergence, randomly interleaved. During each trial, a central LED—situated 40 cm in front of the participant (the same distance from his left and right eye)—is switched on at a random time between 1200 and 1800 ms. Then a nearest LED or a farthest LED is lit for 2000 ms, following an overlap paradigm. These two LEDs are on the same axis as the central LED (the same distance from the left and right eyes of the participant). The nearest LED is situated 20 cm from the participant, calling for a convergence angle of 8.76°. The farthest LED is situated 150 cm from the participant, calling for a divergence angle of 6.5°.Between the trials for the saccade and vergence sequences, a blanked period of 300 ms to 700 ms was applied. All of these values are given with a pupillary distance of 62 mm.The eye movements were recorded binocularly with the head-mounted video-oculography device, Pupil Core .The data recorded with the Pupil Labs eye tracker was analyzed with the AIDEAL software . The signal was derived by calculating the difference between the two eyes from the individual calibrated eye position signals . The onset and the offset of the saccades were defined as the moments where the velocity went above or below 10% of the peak velocity. The onset and the offset of the vergences were defined as the moments where the velocity went above or below 5°/s. These criteria are standard, and were applied automatically by the AIDEAL software. Trials with blinks were excluded.The results are given in an excel spreadsheet and graphs .The Stroop test is a cognitive test assessing executive functions such as selective attention or inhibition capacities. It consists of orally enumerating the font colors of a list of words with a different meaning than their color (ex: the word “blue” printed in red).The brain has to inhibit the information given by the word’s meaning, which is the most protruding and intuitive, to focus on the information given by the printed colors. In other words, it has to focus on specific information while ignoring other information.The Stroop test was first described in 1935 by J.R. Stroop . Many vaIn this article, the selected version of the Stroop test is the French Stroop Victoria . This vemais” (but), “pour” (for), “donc” (thus) and “quand” (when). The third condition is the “Interference” condition, where the items are the words “bleu” (blue), “vert” (green), “jaune” (yellow) and “rouge” (red). The words in this last condition are incongruent, i.e., the color ink of the word is not the same as the word’s signification (example: the word “rouge” (red) printed in green).In this version, the participant has to list the color of 24 items as quickly as possible (6 lines of 4 items) in three different conditions. The possible colors of the items are blue, green, yellow or red. The first condition is the “Dot” condition, where the items are dots. The second condition is the “Word” condition, where the items are the French words “In this article, Stroop_D represents the time to perform the “Dot” condition, Stroop_W represents the time to perform the “Word” condition, and Stroop_I represents the time to perform the “Interference” condition. From these variables are also calculated the Stroop_I/D, which represents the ratio of Stroop_I over Stroop_D; and Stroop_W/D, which represents the ratio of Stroop_W over Stroop_D.Thus, the Stroop Victoria first assesses the speed of color denomination (Stroop_D). Then, it assesses the same variable but in the presence of distracting information, i.e., the meaning of the words (Stroop_W and Stroop_I). The ratios Stroop_W/D and Stroop_I/D represent the behavioral impact of this distracting information on the speed of color denomination. The difference between Stroop_W/D and Stroop_I/D is about the strength of their interference effect. The distracting information given by the “Interference” condition is stronger than that given by the “Word” condition. Thus, the Stroop_W/D assesses the behavioral impact of a weak interference, while the Stroop_I/D assesses the behavioral impact of a strong interference.Besides this, the study of aging’s effect on inhibition and selective attention will be more specific with Stroop_I/D than with Stroop_I. Indeed, if the increase of Stroop_I with age could reflect the loss of selective attention capacities, it can also reflect a general slowing due to age . The age-related general slowing is a robust finding in studies. This behavior slowing appears for motor responses and sensory processes, and becomes more important with complex tasks ,48. The Aging’s effects on hearing, eye movement latency and Stroop scores are measured with simple linear regressions and correlations: Hearing ~ Age, Latency ~ Age, and Stroop ~ Age. These results are presented in the The relationships between hearing, eye movement latency and Stroop scores are investigated two by two: hearing VS eye movement latency, hearing VS Stroop scores and latency VS Stroop scores. As all of these parameters deteriorate with age, the results may be skewed by their confounding effects. In order to avoid this, the simple linear regression will be abandoned in favor of multiple regression analysis, adding age as an explanatory variable: Hearing ~ Latency + Age, Hearing ~ Stroop + Age, and Latency ~ Stroop + Age. These results are presented in the The results are organized as follows: (i) characteristics of the population in terms of hearing and cognition relative to healthy standards; (ii) links between the three hearing scores via Pearson correlation; (iii) aging’s effect on the hearing, eye movement latency and Stroop scores via Pearson correlation; (iv) links between hearing, eye movement latency and Stroop scores via multiple regression analysis.The classification of hearing loss and the Stroop results for Group E are shown in According to the WHO hearing loss scale , Figure These results, discussed below, are in the normal standard for hearing aging. Of the 19 participants of Group Y who passed the hearing tests, none of them had a PTA superior to 20 dB HL or were considered to have hearing issues. To sum up, the hearing and Stroop scores pointed toward a healthy aging population.The results assessing the correlations and regression lines between the different hearing tests for the whole population (Group Y + Group E) are in r = 0.88, p = 0.000). However, the results in r = 0.25, p = 0.035), or SNR50 vs SRT50  are weaker, albeit statistically significant. These results indicate the difficulty of predicting speech-in-noise ability based on pure-tone threshold audiometry.The correlations in Before assessing the interaction between hearing, eye movement latency and inhibition capacities, it is important to analyze their interaction with age. Age is a preponderant factor in this study, and it is known that it affects both of them. This analysis enables us to check whether or not the population is aging normally.The results assessing the correlations and regression lines between the different hearing tests and age for the whole population (Group Y + Group E) and Group E are in The results highlight the global deterioration of hearing capacities across the lifespan. The slopes of the regression lines for the whole population (blue dashed lines) are positive and statistically significant for the audibility A, speechThe results assessing the correlations and regression lines between the different eye movement latencies and age for the whole population (Group Y + Group E) and Group E are in The results in The results assessing the correlations and regression lines between the different Stroop scores and age for the whole population (Group Y + Group E) and Group E are in p inferior to 0.001, “**” for a p between 0.001 and 0.01, “*” for a p between 0.05 and 0.01, and “.” for a p between 0.1 and 0.05. The column “cor” gives the Pearson correlation values.The results of the linear regressions and the correlation of the different Stroop scores as a function of age are shown in Regarding the results for the whole population , and the percentage of participants who presented a hearing deficit was in the expected rates. The study of Lin et al.  found a Concerning the eye movement latency, the results of the current study also show a degradation of the latency for all of the eye movements measured . For saccade, these results are in line with the literature ,28,29,30Concerning the Stroop scores, the results show a progressive deterioration with age of Stroop_I and Stroop_I/D for the whole population (Group E + Group Y) and for Group E alone. The Stroop_I scores are in line with the literature ,38,39,40To sum up, the results are globally consistent with the literature, showing a deterioration of hearing, latency and inhibitory capacity with age, suggesting that the aging effects described and the interactions described below may arise from physiological mechanisms. Moreover, all of the participants were autonomous or still-active professionals, and were carefully prescreened to exclude individuals with any type of pathology .Now, we will discuss the possible implications of the study’s major findings.Presbycusis, and more generally hearing issues, are mostly determined in the clinic using three hearing tests: pure-tone audiometry thresholds, speech audiometry in silence and speech audiometry in noise. Although pure-tone audiometry thresholds have been the gold standard for the measurement of hearing impairment for roughly 100 years, it has become more obvious in the last few years that they can miss specific hearing issues, which are called “hidden hearing loss” . This kiThus, presbycusis can degrade the audibility (which is assessed by pure-tone audiometry) and sound processing  in independent ways, and speech audiometry in silence and in noise is now systematically assessed in hearing evaluation. It is noteworthy that, in France, recent regulation enables the reimbursement of hearing aids by social security in the presence of an abnormality of either PTA or speech recognition in silence or noise.r = 0.86, p = 0), but this is largely due to the method used to measure speech comprehension ability in silence. Indeed, PTA measures audibility , and SRT50 also strongly depends on it. SRT50 only measure one characteristic of speech comprehension: the minimal intensity required from a word to be approximately understood (50% comprehension). For example, a participant with a bad PTA will also have a bad SRT50 because he wouldn’t even detect the words with low intensity. Even given this, there is still around 25% of the variability of the SRT50 that the PTA doesn’t explain. The results in In the current study, PTA and SRT50 are strongly correlated  between SNR50 and PTA is in line with the literature: pure-tone audiometry is not a good predictor of speech-in-noise audiometry. In this way, people who normally detect sound can have abnormal difficulties in understanding in noisy environments ,59,60,61However, even these three measures together are far from representing our total hearing abilities. PTA, SRT50 and SNR50 do not fully represent audibility and speech comprehension abilities in silence and in noise. For example, PTA is limited to a few frequencies . SRT50 represents only one characteristic of the speech comprehension ability, i.e., the minimum intensity required to obtain 50% comprehension in silence, for a specific setup, and when the subject is fully focused on that task. Even if other variables than SRT5 can be extracted from speech audiometry in silence, this test does not assess, for example, the listening effort required or the mental replacement. The same problems apply to SNR50. Moreover, it is even more difficult for speech audiometry in noise to provide an accurate reflection of the real situations, as it is very difficult to recreate a noisy environment in a sound booth cabin, and there are many different noisy situations. In that respect, research on additional tools for hearing issue diagnosis is of high interest.The major finding of the current study, i.e., the significant link between SRT50 and the saccade latency independently from age, suggests a promising way forward for further research. As PTA and SRT50 are highly correlated, it is interesting to note that saccade latency is significantly associated with SRT50 but not with PTA. The difference between them is that SRT50 not only relies on audibility but also on speech processing.Thus, we hypothesize that saccade latency reflects, in some way, the speech processing abilities, and may become a diagnostic tool for it. Further studies on that topic would be interesting if they took other setups allowing a better focus of the speech processing abilities to the detriment of audibility. However, apart from such potential interests to develop other clinical tools of presbycusis diagnosis, the question is which mechanisms underlie such an association between saccade latency and speech processing.As mentioned in the introduction, the activated mechanisms during eye movement latency—i.e., attention, motor preparation and decision—are highly related to cognitive executive functions, and are subtended by a wide cortical visual parietal frontal network. This is confirmed by literature that found an association between saccade latency and cognitive health ,34,35. TNone of the Stroop scores assessed here were significantly related to hearing abilities, whether this is PTA, SRT50 or SNR50, suggesting that selective attention is not relevant for hearing processing. However, there is already existing literature suggesting that inhibition and selective attentional capacities (measured with Stroop tests) have an important role in speech comprehension ,62. The Concerning the first assumption, the background noise used in the study of Janse et al.  was distTo sum up, saccade latency seems to be a promising new approach to estimate and measure the cognitive process involved in speech processing.These mechanisms didn’t appear to be related to the selective attention involved in a visual task. However, this last assumption required further research. It would be interesting to use an inhibition test implying auditory modality, as was shown in the studies of Sommers et al., or to use the Visual Stroop test with other paradigms.This is a pioneering study on the relationship between the normal aging of eye movement latency, hearing and cognition capacities. The auditory and cognitive consequences of presbycusis are of high importance, and current hearing tests sometimes may not be sufficient to accurately evaluate hearing capacities ,59,60,61REMOBI: US885 1669, WO2011073288, AIDEAL: PCT/EP2021/062224 7 May 2021.


Untreated age-related hearing loss increases audiovisual integration and impacts resting state functional brain connectivity. Further, there is a relation between crossmodal plasticity and audiovisual integration strength in cochlear implant patients. However, it is currently unclear whether amplification of the auditory input by hearing aids influences audiovisual integration and resting state functional brain connectivity. We conducted a randomized controlled pilot study to investigate how the McGurk illusion, a common measure for audiovisual integration, and resting state functional brain connectivity of the auditory cortex are altered by six-month hearing aid use. Thirty-two older participants with slight-to-moderate, symmetric, age-related hearing loss were allocated to a treatment or waiting control group and measured one week before and six months after hearing aid fitting with functional magnetic resonance imaging. Our results showed a statistical trend for an increased McGurk illusion after six months of hearing aid use. We further demonstrated that an increase in McGurk susceptibility is related to a decreased hearing aid benefit for auditory speech intelligibility in noise. No significant interaction between group and time point was obtained in the whole-brain resting state analysis. However, a region of interest (ROI)-to-ROI analysis indicated that hearing aid use of six months was associated with a decrease in resting state functional connectivity between the auditory cortex and the fusiform gyrus and that this decrease was related to an increase of perceived McGurk illusions. Our study, therefore, suggests that even short-term hearing aid use alters audiovisual integration and functional brain connectivity between auditory and visual cortices. In this study, we showed that first time hearing aid use of six months was related to a decrease in resting state functional connectivity between the auditory cortex and the fusiform gyrus. The decreased connectivity was associated with an increase in perceived McGurk illusions. Further, this increase in McGurk illusions was correlated with decreased hearing aid benefit in auditory speech in noise intelligibility. Our study therefore suggests that hearing aid fitting impacts functional connectivity between auditory and visual regions and audiovisual integration (susceptibility to the McGurk illusion). Further our results suggest, that an increased McGurk susceptibility seems to inhibit the beneficial effect of the hearing aid when tested in auditory only conditions.One of the most prevalent chronic disorders in older adults is age-related hearing loss (presbycusis), a form of bilateral sensorineural hearing loss that is caused by damage to the cochlea or the auditory nerve and predominantly affects high frequencies. One of the primary treatments for presbycusis is amplification of the auditory input through hearing aids. The use of hearing aids is associated with self-reported improvements in communication because of increased speech clarity , improvePresbycusis is often associated with an increased cross-modal plasticity referring to an increased neural activity in the auditory cortex when processing visual stimuli. Although mainly described in deafness , crossmoPrevious studies also revealed that hard-of-hearing participants perceived the McGurk illusion significantly more often than normal-hearing individuals . The McGIncreased task-modulated functional connectivity between auditory and visual cortex, when comparing incongruent (McGurk) with congruent audiovisual stimuli, was found in hard-of-hearing compared with normal-hearing participants . MoreoveTherefore, the aim of the current study was to investigate how the McGurk illusion and resting state functional connectivity are altered by hearing aid use in age-related hearing loss. For this purpose, we conducted a pilot randomized controlled hearing aid fitting study in which 16 hard-of-hearing participants were measured one week before and six months after first fitting of a hearing aid (treatment group). The other 16 hard-of-hearing participants were not equipped with a hearing aid and were measured twice at an interval of six months as well (waiting control group). We expected a decrease in the number of McGurk illusions in the treatment compared with the control group . Moreoven = 163 participants between 60 and 80 years of age with self-reported hearing loss and no prior hearing aid experience. Inclusion criteria were a slight-to-moderate, symmetric, age-related hearing loss defined as better-ear pure-tone averages (PTAs) across the frequencies 0.5, 1, 2, and 4 kHz between 18 and 56 dB HL , and the study was conducted in accordance with the Declaration of Helsinki as well as the European Union General Data Protection Regulation. All subjects signed a written informed consent form and were paid for participation.Treatment and control group were stratified with respect to hearing impairment (PTA), age and cognitive performance  starting with the simplest approach by (1) trying to master gain, (2) frequency-dependent gain, (3) compression, and (4) allowing for additional noisy-environment program only if the subject explicitly required it. All changes were documented. The participants were instructed to wear their hearing aids daily for at least 6 h and gave their written consent to log the data of the hearing aid. The waiting control group was offered a hearing aid fitting by the Hörzentrum Oldenburg GmbH after the study was completed.Participants in the treatment group were fitted with bilateral Signia Pure 7Nx/px hearing aids with M-receivers and click dome (semi-) open coupling by trained acousticians at the Hörzentrum Oldenburg GmbH. For the fitting formula, NAL-NL2 with fixed pinna-preserving Omni-Mode and default noise reduction was set as default. For all fittings, All participants underwent behavioral and MRI measurements one week prior and six months after potential hearing aid fitting. Participants in the treatment group were additionally assessed one month after the fitting (data not reported).The individual pure-tone audiograms for the baseline and six-month postassessment are shown in Behavioral measurements included a pure-tone audiometry, cognitive screening [Montreal Cognitive Assessment (MOCA), Pure tone audiometry was performed in a soundproof chamber using air conduction pure-tone audiometry for the frequencies 125, 250, 500, 1000, 2000, 4000, 6000, and 8000 Hz.2; refresh rate: 60 Hz) and via Sennheiser HDA200 headphones delivered by the USB audio interface RME Fireface UC (http://www.rme-audio.de/en/products/fireface_uc.php). Stimulus presentation was controlled by Presentation software . The task consisted of typical McGurk syllables that were presented as either auditory-only, visual-only, audiovisual congruent, or audiovisual incongruent conditions (the McGurk illusion). We used the syllables ‘ga’ and ‘ba,’ which commonly lead to the fused percept ‘da’ when presented as incongruent stimuli . These stimuli were a subset of syllables that were recorded in the Department of Media Production at the University of Oldenburg and consisted of video and audio files of a male speaker articulating the different syllables in front of a dark gray background . Participants had to fixate a white fixation dot that was presented on a black screen. The fixation dot was presented with the Presentation software  via a projector behind the bore of the MRI . Anatomical images were acquired with a 3-D T1-weighted sequence .To assess general task performance in the McGurk task, we computed mean performance measures (% correct) for audiovisual congruent conditions , auditory-only and visual-only conditions for each participant. Potential differences in general task performance between groups at baseline and after six months were assessed by repeated-measures general linear model (GLM) on the percent of correctly identified syllables with condition  as within-subject factor and group (treatment/control) as between-subject factor.To assess audiovisual integration, the incongruent McGurk (illusion) trials underwent a detailed analysis to investigate potential group differences in the susceptibility to the McGurk illusion (defined as fusion reports ‘da’). Since the response options in the incongruent condition can be either the auditorily-presented syllable (‘ba’), the visually-presented syllable (‘ga’) or the fused illusion percept (‘da’), a first analysis focused on the percent for each response option across SOAs using a repeated-measures GLM with group as between-subject and response as within-subject factors (for baseline and after six months). A second analysis focused on the fused percept as a function of SOA using a repeated-measures GLM with group as between-subject and SOAs within-subject factors (for baseline and after six months).post hoc correlation analyses were performed to investigate (1) whether the McGurk susceptibility is a valid measure of audiovisual integration  and (2) whether the change in the McGurk susceptibility is a positive or negative outcome for speech intelligibility (correlation of the change in McGurk susceptibility between baseline and retest assessment with benefit of aided vs unaided speech intelligibility).Two Resting state functional connectivity data were analyzed with the Statistical Parametric Mapping software package  based on MATLAB 2016b and the CONN toolbox . Images x = −44, y = −11, z = 34) provided by The main seed in this study was positioned in the left and right Brodmann areas 41 and 42  ROI-Library within the WFU Pickatlas). This pooled seed was used for the whole-brain analysis and for the ROI-to-ROI analysis. The fusiform gyrus was used as a ROI because of its involvement in face processing  and its p < 0.001 and a cluster corrected threshold of pFWE < 0.05. For the ROI analysis, connectivity values between (1) the auditory cortex and the fusiform gyrus as well as (2) the auditory cortex and the M1 lip area  were extracted. Changes in connectivity values from auditory to fusiform and the M1 lip area between measurement time points were compared across groups (using repeated-measures ANOVAs) and correlated with changes in the McGurk illusion (Pearson correlation). These analyses were computed in JASP .In order to assess changes in functional resting state connectivity of the auditory cortex to the rest of the brain after hearing aid fitting, we computed an interaction between group (treatment/control) × measurement time point (baseline/after six months) with a height threshold of Although all participants were instructed to wear the hearing aid for at least 6 h/d, the average daily wearing period ranged from 1 to 12 h, with a median of 7 h. Given the small number of subjects we refrained from excluding three subjects who had been wearing their hearing aids for <5 h/d as none of them had been detected as an outlier during the analysis.F = 34.49, padj < 0.001, GGeps = 0.76, η2p = 0.54; after six months: F = 44.75, padj < 0.001, GGeps = 0.78, η2p = 0.61), whereas neither the main effect of group nor the group × condition interaction yielded significance. Hence, general task performance did not differ between the treatment and control group for neither baseline nor re-test assessment. Post hoc comparisons showed that both groups performed significantly better in both the auditory-only and audiovisual congruent condition than in the visual-only condition .The mean performance values for both groups and measurements for audiovisual congruent, auditory-only, and visual-only conditions are presented in To assess changes in audiovisual integration we analyzed the amount of McGurk illusions (‘da’ response), auditory (‘ba’), and visual (‘ga’) percepts in incongruent trials for each group at both measurement time points  = 23.47, padj < 0.001, GGeps = 0.55, η2p = 0.45; response × group: F = 2.96, padj = 0.055, GGeps = 0.55, η2p = 0.092). As presented in After six months, we again found a main effect of response together with a significant trend for a response × group interaction with a medium effect size  and the auditory response  than for the visual response .The correlation between responses given at baseline and responses given after six months for all participants was significantly correlated for all three response options, while the correlation was stronger for the McGurk illusion  = 17.19, padj < 0.001, GGeps = 0.52 η2p = 0.36), whereas neither the main effect of group nor the SOA × group interaction were significant. Hence, although the treatment group showed slightly higher values in the amount of McGurk illusions at baseline, those differences were not statistically significant.To assess potential group differences and changes in the McGurk illusion as a function of SOA, we first looked at the baseline assessment. As expected, the main effect of SOA was significant with decreasing illusion reports with increasing SOAs  = 18.07, padj < 0.001, GGeps = 0.29, η2p = 0.38; group: F = 3.97, p = 0.05, η2p = 0.12). The treatment group showed more McGurk illusions than the untreated peers.At the re-test assessment, we found a significant main effect of SOA together with a significant trend for a main group effect with a medium effect size  whether the McGurk susceptibility is a valid measure of audiovisual integration and (2) whether the change in the McGurk susceptibility is a positive or negative outcome for speech intelligibility. The results for the speech intelligibility task can be seen in p > 0.1).Two r = −0.457, p = 0.075), indicating better audiovisual speech intelligibility with higher number of McGurk illusions. The same correlation was not significant after six months . As a next step, we computed a correlational analysis for the treatment group only, evaluating the benefit of aided versus unaided measurement conditions and the change in McGurk susceptibility over time. While this analysis showed a positive correlation for the auditory speech intelligibility .We conducted a functional connectivity analysis of the auditory cortex (left and right Brodmann areas 41 and 42) to the whole brain at baseline and after six months see . The audF = 7.566, p = 0.01, η2 = 0.142; F = 0.538, p = 0.469, η2 = 0.007; In the second step, we implemented a ROI analysis and extracted functional connectivity values between the ROIs in the auditory cortex (left and right Brodmann areas 41 and 42) and the fusiform gyrus as well as between the auditory cortex and the M1 lip area  for each group and measurement time point (baseline and after six months). The interaction between group and measurement time point with respect to functional connectivity of the auditory cortex and the fusiform gyrus was significant , but not in the control group  in a sample of 165 participants  × measurement time point (baseline/after six months). We hypothesized a decrease in functional coupling of the auditory cortex to visual brain regions after hearing aid use of six months . This hySurprisingly, the decrease in functional coupling was linked to an increased number of perceived McGurk illusions after six months of hearing aid use in the treatment group. In other words, we found that hearing aid use was associated with (1) a decrease in resting state functional connectivity between auditory and fusiform brain regions, and (2) that this decrease in connectivity was linked to an increase in McGurk illusions. A recent study demonstrated that hard-of-hearing participants compared with normal-hearing participants showed an increased task-modulated functional connectivity between auditory and visual cortex for McGurk as compared with congruent audiovisual stimuli . Other rCrossmodal plasticity in the auditory cortex has mainly been described in deafness , but alsMoreover, crossmodal plasticity has not only been shown in terms of neural activity in the auditory cortex, but there are several studies assessing functional connectivity of the auditory cortex during different tasks  or restiIt seems that hearing aid use in age-related hearing loss is associated with observable neural changes in the auditory cortex that are linked to an increased McGurk illusion response already after a relatively short period of six months. However, we need to point out some limitations of the current study. On the behavioral level, some of the behavioral results were only significant at trend level . This may be because of the small sample sizes and the large variability in the McGurk illusion. A complicating factor that may also serve as an explanation for that result is the fact that the McGurk illusion in the treatment group was only tested in an unaided condition. We chose to measure the treatment group in an unaided condition to enable comparability between groups and to assess potential general changes that are not associated with specific hearing aid settings. Although the level of stimulus presentation was individually adapted for all participants, we cannot exclude that this created a rather unusual and difficult listening situation, in which the auditory input was not perceived as reliable as with the hearing aids. Because of time limits, we were unfortunately not able to conduct both aided and unaided assessments. Regarding the resting state connectivity data, we only observed a significant change in resting-state connectivity in our ROI-to-ROI analysis and not in the whole-brain analysis. A possible explanation might be lack of power because of the small sample size. Hence, the interaction between group and measurement time point was shown to be significant in the ROI-to-ROI analysis but might not have survived the correction for multiple comparisons in the whole-brain analysis. Thus, this study can only be seen as a pilot study. However, the results may trigger future research on the influence of hearing aid fitting in age-related hearing loss. How long-term use of a hearing aid (more than one year) influences cross-modal plasticity in mild to moderate hearing loss and how this relates to speech perception outcomes should be investigated by future research. Further, future studies should consider assessing audiovisual integration in aided and unaided conditions in hearing aid users as well as larger group sizes.In conclusion, this is the first study to provide pilot data on the effect of hearing aid fitting on the McGurk illusion and resting state functional connectivity. We demonstrated that hearing aid use is associated with changes in resting state functional connectivity between the auditory cortex and fusiform gyrus, which is also related to the increased number of perceived McGurk illusions. We also found a relation between increased McGurk illusion and decreased hearing aid benefit in auditory speech in noise intelligibility. Our study therefore offers valuable insights into alterations in resting state functional connectivity and changes in audiovisual integration (susceptibility to the McGurk illusion) and speech perception after six months of hearing aid use.


Background: Consensus is lacking with regard to whether hearing loss is an independent risk factor for dementia. We therefore conducted a meta-analysis to clarify the relationship of hearing loss and dementia.Methods: Prospective cohort studies investigating the association between hearing loss and the incidence of dementia in a community-derived population were included by searching electronic databases that included PubMed, Embase, and Cochrane's Library. A random-effects model was adopted to combine the results.Results: Fourteen cohorts including 726,900 participants were analyzed. It was shown that hearing loss was independently associated with dementia . Sensitivity analysis sequentially excluding any of the individual studies included showed similar results. Subgroup analysis according to the diagnostic methods for hearing loss, validation strategy for dementia, follow-up duration, and adjustment of apolipoprotein E genotype also showed consistent results . Meta-analysis with five studies showed that hearing loss was also connected to higher risk of Alzheimer's disease .Conclusions: Hearing loss may increase the risk of dementia in the adult population. Whether effective treatment for hearing loss could reduce the incidence of dementia should be explored in the future. Hearing loss is one of the most common sensory deficits in the elderly population  guideline  “hearing impairment” OR “hearing dysfunction” OR “hearing disorder” OR “hearing loss” OR “deaf” OR “deafness”; (2) “dementia” OR “cognitive decline” OR “cognitive impairment” OR “cognitive dysfunction” OR “Alzheimer” or “Alzheimer's”; and (3) “prospective” OR “prospectively” OR “longitudinal” OR “incident” OR “incidence” OR “risk” OR “followed” OR “follow-up” OR “cohort”. Only studies reported in English were considered. References of related articles or reviews were also analyzed.Studies that fulfilled these criteria were used: (1) prospective cohort studies published as full-length papers, (2) included general adult population, (3) evaluated the association between hearing loss and the incidence of dementia due to any cause or AD during follow-up, and (4) reported hazard ratios (HRs) for the above associations after adjusting for multiple confounding factors (at least for age and sex). Diagnostic criteria of hearing loss, dementia, and AD in the original articles were used. Reviews, preclinical studies, cross-sectional or retrospective studies, and irrelevant studies were not included.Two authors implemented database search, data extraction, and study quality assessment separately. If disagreements occurred, they were discussed with the corresponding author. These data were recorded: (1) author and study year; (2) participant characteristics, including number of participants included, mean age, and sex; (3) methods for the evaluation of hearing loss; (4) follow-up durations; (5) methods for validation of dementia or AD outcomes, and numbers of cases with outcomes reported in each study; and (6) potential confounding factors adjusted in the multivariate analyses. The Newcastle–Ottawa Scale  were extracted for every included study. For studies that reported multiple HRs according to different models of multivariate regression analysis, the most adequately adjusted HR from each study was extracted and combined in this meta-analysis. Then, standard errors (SEs) of HRs were estimated from the 95% CIs or Details of the database search are shown in Characteristics of each study of the meta-analysis are shown in p < 0.001; I2 = 86%; p-values for subgroup differences all >0.05). Pooled analyses with five studies . The funnel plots for the meta-analysis of hearing loss and AD are shown in Funnel plots representing the meta-analysis of hearing loss and all-cause dementia are shown in Results of this meta-analysis showed that hearing loss may be an independent risk factor for dementia in a community-derived general population. Subgroup analyses showed that this association seemed to not be affected by study characteristics such as the diagnostic methods for hearing loss, validation strategy for dementia, follow-up duration, and adjustment of APOE genotype. Although potential publication bias was suggested, a complementary trim-and-fill analysis conducted by incorporating the two hypothesized studies with negative findings showed consistent results with the main meta-analysis. Moreover, we also found a meaningful association between hearing loss and AD. Together, these results suggested that hearing loss may be an independent risk factor for dementia in the general adult population. Whether effective treatment for hearing loss is effective in reducing the incidence of dementia should be further validated.A previous meta-analysis included 40 studies and suggested that age-related hearing loss may be associated with all-cause dementia (Loughrey et al., The studies included in the current work have multiple strengths compared with the previous meta-analyses. First, we only considered prospective cohort studies in our meta-analysis, aiming to minimize the influence of recall biases that could be caused by studies with a retrospective design (Coughlin, To the best of our knowledge, only two previous meta-analyses have evaluated the association between hearing loss and AD (Zheng et al., Results of our study highlight the possibility that alleviation of hearing loss may become a preventative strategy for dementia. The most frequent cause of acquired hearing loss is cochlear damage. Accordingly, amplification with hearing aids or cochlear implants is often effective for these patients (Boisvert et al., This study also has limitations. First, the meta-analysis was based on data from the study level but not from individual patients, which prevented further analyses on the influence of patient characteristics on the outcome. In addition, diagnosis of hearing loss varied among the included studies, and the association between hearing loss and dementia, according to the severity of hearing loss, could not be determined based on the current meta-analysis. Methods for validation of dementia outcomes also varied among the included studies, which may be a source of heterogeneity. Additionally, we included prospective cohort studies only to reduce any potential bias. However, information from cross-sectional or retrospective studies may be missing. Finally, possible risk of publication bias was raised in the meta-analysis regarding the association between hearing loss and dementia. However, further trim-and-fill analysis suggested that the potential publication bias was not likely to affect the finding.In conclusion, this updated meta-analysis of prospective cohort studies suggests that hearing loss is likely to be an independent risk factor of dementia, as well as for AD in the general adult population. Clinical studies are needed to clarify whether effective treatment for hearing loss, such as hearing aids and cochlear implantation, can prevent the incidence of dementia in these patients.The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author/s.ZL, AL, XQ, and XG designed the study. ZL and AL performed literature search, study quality evaluation, and data extraction. ZL, AL, and YX performed the statistical analyses. ZL, AL, XQ, and XG interpreted the results. ZL and AL drafted the manuscript. All authors revised the manuscript and approved its submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Hearing loss is a major unresolved problem in the world, which has brought a heavy burden to society, economy, and families. Hair cell damage and loss mediated by oxidative stress are considered to be important causes of hearing loss. The nuclear factor erythroid 2–related factor 2 (Nrf2) is a major regulator of antioxidant capacity and is involved in the occurrence and development of a series of toxic and chronic diseases associated with oxidative stress. In recent years, studies on the correlation between hearing loss and Nrf2 target have continuously broadened our knowledge, and Nrf2 has become a new strategic target for the development and reuse of hearing protection drugs. This review summarized the correlation of Nrf2 in various types of hearing loss, and the role of drugs in hearing protection through Nrf2 from the literature. Hearing loss is a great challenge for the physical health and communication, which affects 6–8% of the population all over the world. In 1985, only 42 million people suffered from hearing loss, while recent updated statistics revealed that the number has rapidly increased to nearly 500 million . AccordiNuclear factor erythroid-2 related factor 2 (Nrf2) as an important transcription factor in regulating oxidative stress response of cells, plays an important role in maintaining cell redox homeostasis . Nrf2 reIn this review, we delineated the structure, function, and localization of Nrf2 in the animal and human cochlea. Moreover, the correlation summary of Nrf2 is specially focused on the three subtypes of hearing loss, namely NIHL, ARHL, and ototoxic hearing loss. In addition, the current development of drug research on Nrf2 for the prevention and treatment of hearing loss was summarized, and we provided our perspectives on Nrf2 as a strategic target for the prevention and treatment of hearing loss.Nrf2 is a transcription factor encoded by NFE2L2 gene . In bothNrf2 activation is associated with two regulators, Keap1 and Cullin3 (Cul3) . The DLGIn animals, Nrf2 is closely related to various diseases by regulating oxidative stress response . Drug enUnlike animal studies, the role of Nrf2 in human diseases is much less reported. Research on the role of Nrf2 in human diseases mainly focuses on cancer , respiraNrf2 is widely expressed in tissues including brain, retina and inner ear . Nrf2-imIn contrast, animal experiments involving the localization of Nrf2 in the inner ear are well established and reported. Different from the normal human cochlea, in the normal rat cochlea, Nrf2 immune response is only detected in the cytoplasm of hair cells, support cells and spiral ganglion neurons (SGNs), and no immune response occurs in the nucleus . HoweverPeripheral hearing loss is usually divided into conductive hearing loss, sensorineural hearing loss or mixed hearing loss with both conductive and sensorineural hearing loss . Most paOxidative stress caused by auditory trauma is the main pathway of cochlear injury . There iNrf2 is an important factor to resist oxidative stress injury in NIHL . After e−/− mice are more susceptible to noise. In Nrf2−/− mice, the expression levels of Nrf2 target genes  significantly decrease after oxidative stress induction, and the reduction of GSH is also demonstrated  and two SNPs of TGF-β1 gene  are closely related to ARHL in a matched and control study of healthy volunteers and elderly deafness patients  Figure . In GJB2ing loss .Platinum anticancer drugs and aminoglycoside drugs are the main clinical ototoxic drugs . CisplatCisplatin induces HEI-OC1 cell apoptosis, which is mainly manifested in nuclear concentration, DNA ladder and caspase-3 activation . The decThe nuclear translocation and activation of Nrf2 are related to the regulation of other signaling pathways. Mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinase (PI3K) signaling pathways are recognized to be involved in the nuclear translocation and activation of Nrf2 . HoweverNrf2-ARE signaling pathway takes a prominent role in regulating phase II detoxifying and antioxidant genes. HO-1 is a downstream product of Nrf2, which plays an antioxidant, anti-apoptotic and anti-inflammatory role through its products bilirubin/biliverdin and carbon monoxide . HO-1 haSimilar to the ototoxicity induced by cisplatin, ROS mediated oxidative stress loss is one of the main factors of aminoglycosides induced cochlear injury . The ami2O2-induced HEI-OC1 cell damage by promoting autophagy and activation of Keap1/Nrf2 signaling pathway, suggesting that p62 has the potential to serve as an adaptor protein between autophagy and the Keap1/Nrf2 signaling pathway in auditory cells (It is worth mentioning that there is a positive feedback relationship between autophagy and Keap1/Nrf2 signaling pathway . Autophary cells .in vitro. In light of this, there is still a long way to go approach clinical application. In cell or animal experiments involving Nrf2, the hearing protection effect of various drugs is mainly realized by promoting the intracellular translocation of Nrf2 and the increase of its downstream target gene products, which we have listed in Research on hearing protection targeting Nrf2 is ongoing, however, this research is mainly executed on animals and cells in vivo experiments are concerned, the research on the role of Nrf2 in protecting hair cells seems only heading in one direction, showing a single mode of activating Nrf2 after drug administration, promoting the expression of its downstream genes and protecting hair cells from damage.As far as the current in vitro studies, although the differences in the protective effects of different dosages of drugs on hearing loss were explored in some settings and the dose-response curves were plotted, future in vitro studies are indispensable to determine the maximum amount of drugs and the resulting acute and chronic toxicity, including pathological sections of major organs after administration. Moreover, the best route, time and dosage of drug administration need to be further optimized. Ebselen, an old analgesic and anti-inflammatory drug, has been shown to reduce oxidative stress damage in hair cells induced by cisplatin via activating the Nrf2-ARE signaling pathway and increasing the expression of HO-1, NADPH and γ-GCS(Although the interactions between Nrf2 and its downstream gene products and other transcription factors were considered in some studies, the key molecules are still far from enough to fully reveal the complete network involved in Nrf2 regulation after drug administration. In these and γ-GCS. In addiand γ-GCS. In clinand γ-GCS. At presNrf2 has been proved as an important target for the treatment of neurodegenerative diseases, respiratory diseases, digestive diseases, cardiovascular diseases, metabolic diseases and cardiovascular diseases. Meanwhile, a variety of drugs have also been discovered to possess antioxidant effects by regulating the expression of Nrf2. The etiology of hearing loss is complex and unclear. Reducing hearing loss caused by oxidative stress injury is considered as one of the greatest challenges. This review summarized the current studies on the role of Nrf2 in various subtypes of sensorineural hearing loss, and lists the current drug studies that act on Nrf2 for hearing protection or to protect HEI-OC1 cell from injury. However, how Nrf2 regulates ROS changes in hair cells and the upstream and downstream regulatory network of Nrf2 in hair cells are still not fully understood. Studies on the early prevention and treatment of hearing loss through the Keap1-Nrf2-ARE signaling axis are still at the exploratory stage, although the new and effective Nrf2 inducer has been proven effective for hearing protection in animal models. In addition, the safety of Nrf2 inducers or activators also merits more attention.There is an urgent need to clarify the following issues. First, the interactions of Nrf2 with other transcription factors should be further investigated to obtain a network for related drug discovery. Second, the development of better cell, animal models which support a real reflection of the pathological conditions of hearing loss. Third, pre-clinical experiments should be executed deliberately to acquire optimized results for transplantation into clinical trials.


STRC gene, located on chromosome 15q15.3, is one of the genetic causes of autosomal recessive mild-to-moderate sensorineural hearing loss. One of the unique characteristics of STRC-associated hearing loss is the high prevalence of long deletions or copy number variations observed on chromosome 15q15.3. Further, the deletion of chromosome 15q15.3 from STRC to CATSPER2 is also known to be a genetic cause of deafness infertility syndrome (DIS), which is associated with not only hearing loss but also male infertility, as CATSPER2 plays crucial roles in sperm motility. Thus, information regarding the deletion range for each patient is important to the provision of appropriate genetic counselling for hearing loss and male infertility. In the present study, we performed next-generation sequencing (NGS) analysis for 9956 Japanese hearing loss patients and analyzed copy number variations in the STRC gene based on NGS read depth data. In addition, we performed Multiplex Ligation-dependent Probe Amplification analysis to determine the deletion range including the PPIP5K1, CKMT1B, STRC and CATSPER2 genomic region to estimate the prevalence of the STRC-CATSPER deletion, which is causative for DIS among the STRC-associated hearing loss patients. As a result, we identified 276 cases with STRC-associated hearing loss. The prevalence of STRC-associated hearing loss in Japanese hearing loss patients was 2.77% (276/9956). In addition, 77.1% of cases with STRC homozygous deletions carried a two copy loss of the entire CKMT1B-STRC-CATSPER2 gene region. This information will be useful for the provision of more appropriate genetic counselling regarding hearing loss and male infertility for the patients with a STRC deletion.The  The STRC gene, which is located on chromosome 15q15.3 in what is known as the DFNB16 locus, is one of the genetic causes of autosomal recessive mild-to-moderate sensorineural hearing loss3.Congenital hearing loss is one of the most common sensory disorders, occurring in 1 in 700–1000 newborns, with approximately 60% of cases attributable to genetic causesSTRC-associated hearing loss is the high prevalence of long deletions or copy number variations observed on chromosome 15q15.3. Chromosome 15q15.3 contains segmental duplications including five functional genes and three pseudo-genes, PPIP5K1 , CKMT1B , STRC , CATSPER2 , PPIP5K1P1, CKMT1A , STRCP1, and CATSPER2P1. Pseudo-STRC  is located downstream of the STRC gene and shows 98% homology to the functional STRC gene. This high degree of homology makes variant interpretation in the analysis of next-generation sequencing results challenging. STRC-associated hearing loss is a relatively common genetic cause of non-syndromic hearing loss, with an incidence of 5.4–16.1% in hearing loss populations with mixed ethnicity5, 6–11.2% in American hearing loss patients7, 6% in Italian hearing loss patients8, 1.7–2.4% in Japanese hearing loss patients10, 2.6% in Turkish autosomal recessive hearing loss patients11, 10% in Czech mild-to-moderate hearing loss patients12, 10.8% in Korean mild-to-moderate hearing loss patients13, and 6% in GJB2-negative Germany hearing loss patients14.One of the unique characteristics of STRC to CATSPER2, is also known to be a genetic cause of deafness infertility syndrome , which is associated with not only hearing loss but also male infertility, as CATSPER2 plays crucial roles in sperm motility16. Thus, data regarding the deletion range for each patient is important for appropriate genetic counseling in terms of hearing loss and male infertility. Several patterns regarding the deletion range of chromosome 15q15.3 have been reported , with some patients harboring a deletion lacking only the STRC gene with the CATSPER2 gene intact. Thus, the prevalence of the STRC-CATSPER deletion among STRC-associated hearing loss patients is thought to be valuable information.Further, the deletion of chromosome 15q15.3 from n = 9956) and analyzed copy number variations (CNVs) in the STRC gene using NGS read depth data. In addition, we performed Multiplex Ligation-dependent Probe Amplification (MLPA) analysis to determine the deletion range including the PPIP5K1, CKMT1B, STRC and CATSPER2 genomic regions to estimate the prevalence of the STRC-CATSPER deletion, which is causative for DIS among STRC-associated hearing loss patients.In the present study, we performed next-generation sequencing (NGS) analysis for a large number of Japanese hearing loss patients  enrolled in this study from 90 otorhinolaryngology departments nationwide. Peripheral blood samples were obtained and DNA was extracted using a DNeasy blood and tissue kit . Evaluation of HL was performed by pure-tone audiometry for patients aged 4 years or older. The pure-tone average (PTA) was calculated from the audiometric thresholds at four frequencies . The severity of HL was classified into 4 categories: mild (PTA 20-40 dB), moderate (41-70 dB), severe (71-90 dB) and profound (> 91 dB). The average age of participants was 26.5 (range 0 to 105), with 3812 males and 4819 females and 1325 without gender information.Informed written consent was obtained from all subjects (or guardians in the case of minors) prior to participation. This study was approved by the Shinshu University Ethics Committee  and the ethics committees of all other participating institutions. All procedures were performed in accordance with the Guidelines for Genetic Tests and Diagnoses in Medical Practice of the Japanese Association of Medical Sciences and the Declaration of Helsinki.17. In brief, amplicon libraries were prepared by using the Ion AmpliSeq Custom Panel, with the Ion AmpliSeq Library Kit 2.0 and the Ion Xpress Barcode Adapter 1–96 Kit (Life Technologies) according to the manufacturer’s instructions. After amplicon library preparation, equal amounts of the libraries for forty-five patients per one sequence run were pooled. After library preparation, next-generation sequencing analysis was performed using the Ion Proton system with an Ion P1 chip or the Ion S5 system with an Ion 540 chip according to the manufacturer’s instructions. We performed about 230 runs for the sequencing of 9956 patients. The averaged number of reads per sample was 1,684,289 reads  and the average depth of coverage was 667 .Next-generation sequencing was performed for the 63 genes reported to cause non-syndromic hearing loss as described in a previous reportThe sequence data were aligned to the human reference genome sequence (build GRCh37/hg19) using the Torrent Mapping Alignment Program (TMAP). Subsequently, DNA variants were piled up with the Torrent Variant Caller plug-in software included in the Torrent Suit (Life Technologies).18. The missense, nonsense, insertion/deletion, and splicing variants were selected from among the identified variants. Variants were further filtered to retain only those with a minor allele frequency under 1% in several control databases including the 1000 genome database (http://www.1000genomes.org/), the 6500 exome variants (http://evs.gs.washington.edu/EVS/), The Genome Aggregation Database (https://gnomad.broadinstitute.org), the human genetic variation database (dataset for 1208 Japanese exome variants) (http://www.genome.med.kyoti-u.ac.jp/SnpDB/index.html), the 8300 Japanese genome variation database (https://jmorp.megabank.tohoku.ac.jp/202102/) and the 333 in-house Japanese normal hearing controls. All filtering procedures were performed using our previously described original database software19. The pathogenicity of the identified variants was evaluated in accordance with the American College of Medical Genetics (ACMG) standards and guidelines20 with the ClinGen hearing loss clinical domain working group expert specification21. Copy number variant (CNV) analysis was performed according to our previous report22.The effects of the variants were analyzed by using ANNOVAR softwareMLPA analysis was performed to confirm the CNVs identified from the read depth data obtained by next-generation sequencing analysis. MLPA was performed using SALSA MLPA Probe mix P461-A1 and the SALSA MLPA EK1 reagent kit FAM according to the manufacturer’s instructions . MLPA amplicon fragment lengths were analyzed by ABI 3130xl Genetic Analyzer  with the GeneScan 500 LIZ Size Standard . The fragment data were analyzed using Coffalyser.net software (MRC-Holland). We performed two duplicate tests for each sample.STRC gene, which were observed in 1093 cases . Among the 612 cases with a 1 copy number loss of the STRC gene, 41 cases carried single nucleotide variants (SNVs) or small insertion/deletion variants in the trans allele configuration. In addition to the 41 cases with SNVs or small ins/dels in the trans allele with the single copy loss of STRC, 1 case had compound heterozygous SNVs and 3 cases had homozygous SNVs. The SNVs or small insertion/deletion variants identified in this study are summarized in Table STRC-associated hearing loss in this study, with the prevalence in Japanese hearing loss patients being 2.77% (276/9956) among all patients, 3.29% (192/5831) among autosomal recessive or sporadic hearing loss cases and 0.87% (18/2069) among autosomal dominant hearing loss cases. The STRC-associated hearing loss identified from autosomal dominant families is caused by pseudodominance as we previously reported9. When we restricted the patients to those with mild-to-moderate hearing loss, the prevalence of STRC-associated hearing loss was increased to 4.27% (132/3088). In addition, we identified only 2 cases with STRC-associated hearing loss among severe-to-profound hearing loss patients . These two cases carried both a homozygous STRC deletion and a biallelic mutation of the GJB2 gene. The severe-to-profound hearing loss observed in these two cases reflects the clinical phenotype of GJB2-associated hearing loss. This observed overlapping of both of the GJB2 and STRC biallelic mutation is thought to result from the high carrier frequency of both of the GJB2 mutations and the STRC deletion.In this study, we performed large-cohort next-generation sequencing analysis and CNV analysis for 9956 Japanese hearing loss patients. As a result, we identified 1258 (12.6%) patients carrying CNVs in 63 previously reported deafness genes. The most prevalent CNVs identified in this study were those in the STRC-associated hearing loss. Many patients in this study were too young to undergo pure-tone audiometry. We also excluded the patients without hearing thresholds information and two severe-to-profound hearing loss patients carrying both of GJB2 and STRC biallelic mutations. Figure STRC-associated hearing loss is congenital-onset, non-progressive, mild-to-moderate hearing loss.In this study, we collected the hearing thresholds for 7 frequencies  by pure-tone audiometry for 159 patients with STRC gene deletions identified using the NGS data, we performed MLPA analysis for 140 randomly selected patients with a 2 copy number loss and 18 patients with a 1 copy number loss of the STRC gene and SNVs using a commercially available MLPA probe set (SALSA MLPA Probemix P461-A1 DIS). As a result of the MLPA analysis, we identified 11 types of deletion pattern for cases with a 2 copy number loss , followed by a 2 copy number loss of the CKMT1B-STRC gene region with a 1 copy number loss of the CATSPER2 gene in 12.9% of cases (18/140). In addition, several complex deletion or duplication patterns were observed in some cases. Among 108 cases with a 2 copy number loss of the whole CKMT1B-STRC-CATSPER2 gene region, 56 cases were female and 52 cases were male. Thus, the prevalence of DIS in patients with hearing loss associated with a 2 copy number loss of the STRC gene was 37.1% (52/140).To confirm the STRC gene (a 2 copy number loss) in 231 of 9956 Japanese hearing loss patients , and 41 cases with a 1 copy number loss of the STRC gene which also carried SNVs in the trans allele configuration. We also identified 4 cases with homozygous or compound heterozygous SNVs; thus, the prevalence of STRC-associated hearing loss in Japanese hearing loss patients was 2.77% (276/9956). In our previous study, we identified 17 of 1025 (1.7%) Japanese hearing loss patients carrying homozygous STRC deletions9. Based on micro-droplet digital PCR analysis, Ito et al. reported that 2 of 84 (2.4%) Japanese mild-to-moderate hearing loss patients carried a homozygous STRC deletion10. Similarly, the prevalence of STRC-associated hearing loss has been reported to range from 5.4 to 16.1% in hearing loss patients of mixed ethnicity, and in American and Italian populations8, 2.6% in Turkish autosomal recessive hearing loss patients11, and 10% and 10.8%, respectively, in Czech and Korean mild-to-moderate hearing loss patients13. From these reports, STRC-associated hearing loss is concluded to be a relatively common cause of hearing loss in every ethnic population. We previously reported the carrier frequency of the STRC deletion in Japanese controls with normal hearing to be 2.6% (4/152)9. Ito et al. reported the carrier frequency of the STRC deletion in Japanese controls with normal hearing to be 0.9% of (1/107)10, whereas Hoppman et al. estimated the carrier frequency of the STRC deletion in controls with normal hearing to be 1%23.In this study, we identified homozygous deletions of the STRC-associated hearing loss patients exhibited mild-to-moderate hearing loss that did not progress up to the age of 60 . Thus, most of the homozygous STRC deletions associated hearing loss cases carried a 2 copy number loss of the whole CKMT1B-STRC-CATSPER2 gene region. Among 108 cases with a 2 copy loss of the whole CKMT1B-STRC-CATSPER2 gene region, 52 cases were male and the prevalence of DIS in patients with hearing loss associated with a 2 copy number loss of the STRC gene was estimated to be 37.1% (52/140). Unfortunately, the main symptom of our study cohort was hearing loss and the data were collected from otolaryngology departments; thus, only limited information was obtained regarding male infertility. The phenotype-genotype correlation between our MLPA results and male infertility, therefore, remains unclear. However, a non-negligible portion of patients with homozygous STRC gene deletions carried the intact CATSPER2 gene. Thus, the determination of the deletion range for STRC-associated hearing loss patients should be performed to allow more appropriate genetic counseling in terms of hearing loss and male infertility. It is noteworthy that the commercially available MLPA probes for DIS are designed for only exons 19 to 25 of the STRC gene and did not identify a partial deletion of exons 1 to 18 of the STRC gene. Indeed, we could not identify STRC gene deletions for 4 cases with partial deletions of the STRC gene  with a homozygous STRC deletion carried a two copy number loss of the whole CKMT1B-STRC-CATSPER2 gene region. This information will be useful in allowing more appropriate genetic counseling regarding hearing loss and male infertility for patients with STRC deletions.In conclusion, we herein report that the prevalence of Supplementary Information.