Precise and timely evaluation of an individual’s hearing loss plays an important role in determining appropriate treatment strategies, including medication and aural rehabilitation. However, currently available hearing assessment systems do not satisfy the need for an objective assessment tool with a simple and non-invasive procedure. In this paper, we propose a new method for pure-tone audiometry, which may potentially be used to assess an individual’s hearing ability objectively and quantitatively, without need for the user’s active response. The proposed method is based on the auditory oculogyric reflex, where the eyes involuntary rotate towards the source of a sound, in response to spatially moving pure-tone audio stimuli modulated at specific frequencies and intensities. We quantitatively analyzed horizontal electrooculograms (EOG) recorded with a pair of electrodes under two conditions—when pure-tone stimuli were (1) “inaudible” or (2) “audible” to a participant. Preliminary experimental results showed significantly increased EOG amplitude in the audible condition compared to the inaudible condition for all ten healthy participants. This demonstrates potential use of the proposed method as a new non-invasive hearing assessment tool. Hearing loss is one of the most common health problems affecting the lives of elderly adults ,2,3,4 anAudiometry measures frequency-specific hearing thresholds  and clasThere are several audiometry systems used to evaluate hearing ability and many researchers have tried to develop accurate, reliable, and fast methods to estimate hearing thresholds. Among them, pure-tone audiometry (PTA) testing has been the most widely used for more than six decades and is considered the “gold standard” in this field ,15,16. PHowever, the current PTA system has some drawbacks that may introduce errors into hearing threshold levels. Since hearing threshold levels are estimated from the subject’s behavioral and psychological data, the traditional PTA system may be (1) dependent on certain variables, such as attention span and reaction time, (2) open to manipulation by examiner’s mistakes or malingerers, and (3) ill-suited for young children who are not mature enough to participate ,22,23. AIn this paper, we propose a concept for a novel hearing assessment method based on quantitative analysis of an electrooculogram (EOG) , which hA total of ten healthy young participants  participated in this study. All participants were students attending Hanyang University and had no medical history or clinical diagnosis of brain injury or tinnitus. Each participant was verbally informed of the detailed experimental protocol and signed a consent form prior to the experiment. Monetary reimbursement was provided to each participant after completion of the experiment. This study was approved by the Institutional Review Board of Hanyang University and was conducted in accordance with the Declaration of Helsinki. All experimental procedures and methods were carried out within approved guidelines.The experimental procedure was designed to investigate the relationship between eye movements when the participants listened to spatially moving pure-tone auditory stimuli and pure-tone thresholds (PTTs) obtained through conventional PTA tests.The entire experiment was divided into two parts and conducted by two examiners. In the first part of the experiment, denoted as part I and was composed of eight repeated sessions, the proposed EOG-based audiometry method was tested. Each session started with a 5 s verbal introduction , asking the participants to close their eyes and concentrate on the moving sound, followed by 16 consecutive EOG recording trials. The duration of each trial was set to 6 s and inter-trial interval was set to a random duration of 2–5 s. In the first trial , no sound was presented for the “no-sound condition”. Then, different combinations of frequencies  and sound intensities  created 15 different sound stimuli. For Trails 2–6, 1000 Hz pure-tone sound stimuli with five different sound intensities were presented in a randomized order. For Trials 7–11, 2000 Hz stimuli were presented, and for Trials 12–16, 4000 Hz stimuli were used.In the second part of the experiment (denoted as part II), two examiners assessed each participant’s air-conduction hearing threshold at the same frequencies used in part I  using a conventional PTA with a modified Hughson-Westlake ascending-descending procedure through a “up 5 dB–down 10 dB” technique. All participants underwent the entire test procedure twice per examiner. Results were double-blind during the experiments and collected afterwards by one examiner. Note that all participants participated in both experiments I and II.Spatially moving sound stimuli presented in the experiments were generated using MATLAB R2016b . We first generated pure-tone sound signals with corresponding frequency and intensity (referred to as “target intensity” in this study) for each trial. In To record a horizontal EOG signal, a pair of flat Ag/AgCl electrodes were placed approximately 2.5 cm away from the lateral canthi of the eyes . The EOThe Digital Audiometer program , a computer-based PTA, was used for part II. Before part II started, the program was calibrated to 60 dB at 1000 Hz using a sound-level meter .Each participant was required to wear noise reduction earplugs to raise their individual hearing threshold level above background noise (20–25 dBA) and to obtain a sufficient amount of data for inaudible conditions. Both parts of the experiment were conducted in a soundproof booth with the participants’ eyes closed. Examiners managed experiments outside the soundproof booth and monitored each participant through a window. All instructions and pure-tone stimuli were given through headphones .EOG data obtained from the experiments was processed using MATLAB R2016b. EOG data were down-sampled to 512 Hz and a horizontal EOG shift was calculated by subtracting electric potential recorded at the right EOG electrode from that at the left EOG electrode. The mean value (DC offset voltage) of each EOG epoch  was then subtracted from the EOG shift to remove the gross DC offset component. A fourth-order Butterworth zero-phase band-pass filter with cut-off frequencies of 0.2 and 0.4 Hz was applied to extract eye movement components, owing to the moving sound source from the pre-processed EOG. Note again that the speed of the moving sound stimulus was set at 1/3 Hz.To compare EOG waveform patterns in inaudible and audible sound intensities, we first classified EOG data into two groups based on PTT results from part II. Note that we only considered trials with intensities below or above PTA thresholds. In other words, trials with exactly the same intensity as the PTA threshold were discarded from analysis.Differences of EOG waveforms recorded under two conditions (inaudible and audible), were quantitatively compared using EOG amplitude, defined as the maximum absolute value in each trial. Sounds with intensities above and below PTTs were referred to as audible and inaudible sounds respectively. EOG amplitudes were normalized by dividing them by the EOG amplitude acquired for 70 dB and the 2000 Hz condition. Note that all participants could hear the auditory stimulus with 70 dB intensity and 2000 Hz frequency. In each session, normalized EOG amplitudes were averaged for inaudible and audible conditions, respectively. Since the total number of repeated sessions was eight, eight EOG amplitude values obtained for the inaudible condition and eight EOG amplitude values for the audible condition were statistically compared using Wilcoxon signed rank test. SPSS ver. 24.0  was used for statistical analyses.p < 0.05). After applying the Bonferroni multiple comparison correction, statistical analysis exhibited significant difference (p < 0.05) between inaudible and audible conditions in all participants. These results suggest that the proposed EOG-based audiometry method has potential to be used as a new tool for assessing hearing loss.The aim of this study was to introduce a new audiometry system that uses a biosignal EOG, indirectly evoked by an individual’s attention to a rotating sound. We found that an individual’s eyeballs involuntarily rotate when he or she is effortlessly listening to a spatially moving pure-tone sound stimuli with different intensities and frequencies with his or her eyes closed. This phenomenon is a kind of auditory oculogyric reflex (involuntary rotation of the eyes toward the source of a sound) and can be readily measured using two horizontal EOG electrodes attached outside the lateral canthi of the eyes. Results of quantitative analysis demonstrated that EOG amplitude was significantly increased when a pure-tone sound was presented at audible frequencies and intensities, compared to EOG amplitude when the sound stimulus was not audible.Although the present study showed the possibility of using EOG to assess an individual’s hearing loss, several issues remain to be addressed in future studies. First, the current system needs to be developed further to classify an individual’s audibility with high accuracy. Establishing standardized cut-off values or parameters to discriminate between audible and inaudible conditions seems to be ideal. However, large inter-individual variability of EOG potential level ,28 needsSecond, normalized EOG amplitude could be dependent on the reference value (maximum EOG amplitude for a pure tone stimulus with 2000 Hz frequency and 70 dB intensity). For instance, amplitude box plots of participant two and six showed relatively longer whiskers and tails in Third, the current method cannot assess the hearing ability of each ear (either left or right ear) separately. To implement such a system, it may be necessary to adjust sound intensity for each ear to different levels when generating moving sound stimuli. However, this procedure would require more test trials, eventually leading to increased test time. Development of more efficient testing schemes would be necessary to make the proposed method more practical. Indeed, we recorded EOG signals for all possible combinations of frequencies and intensities, rather than following the most common PTA procedure, namely, a modified Hughson-Westlake ascending-descending method. Reducing the duration of each trial is also required to enhance overall efficiency of the proposed method. Although only three frequencies corresponding to speech understanding were tested in this study, testing a wider range of frequencies, including those used in standard PTA would be necessary in future investigations. Most importantly, general applicability of the proposed EOG-based audiometry needs to be verified by testing with hearing impaired patients, such as elderly people who have general degenerative processes of the neurologic system and children.Despite these limitations, the present proof-of-concept study demonstrated the potential of a new PTA system based on EOG, as a new non-invasive hearing assessment. After improving overall performance of the proposed audiometry system, it would be necessary to compare advantages and disadvantages between the proposed method and conventional objective audiometry methods, such as brainstem evoked response audiometry (BERA) and the otoacoustic emission (OAE) test. BERA is a hearing assessment method that uses small auditory evoked potentials recorded from a few electrodes attached to the scalp surface. The brainstem auditory evoked potential (BAEP) method is composed of seven waves and is clinically analyzed based on morphological characteristics such as absolute latency, wave amplitude, and inter-peak interval latency. Although both BERA and the proposed audiometry have a common advantage over conventional PTA in that they do not require the subject’s active participation, the proposed EOG-based audiometry is expected to be implemented more easily and more cheaply than BERA, considering that amplitude of EOG is generally much larger than that of BAEP. Because of the small amplitude of BAEP, repeated presentations of auditory stimuli  are required to acquire clean BAEP waveforms . OAE is Please note that the proposed hearing assessment method did not fully overcome all problems of conventional PTA. For example, the proposed method can also be dependent on attention of the subjects. In addition, EOG signals might be contaminated by movement-related artefacts when the proposed method is used for hearing assessments of young children, who might have difficulty staying still during the recording session. Therefore, further work should be done to implement a more reliable and efficient EOG-based audiometry system that can be used in practical scenarios. In addition, development of a low-cost portable EOG recording device incorporated with an audio headset would foster better accessibility of the proposed audiometry system.


The retina is a complex, multilayered tissue responsible for the perception of visual stimuli from the environment. Contrary to mammals, the capacity for postnatal eye growth in fish and amphibians, and to a lower extent in birds, is coordinated with a progenitor population residing in the ciliary marginal zone (CMZ) at the retinal peripheral margin. However, little is known about embryonic retinogenesis and postnatal retinal growth in squamates , despite their exceptional array of ecologies and ocular morphologies. Here, we address this gap by performing the first large‐scale study assessing both ontogenetic and adult changes in the stem/progenitor activity of the squamate peripheral retina. Our study reveals for the first time that squamates exhibit a source of proliferating progenitors persisting post embryogenesis in a newly identified retinociliary junction anteriorly adjacent to the retina. This region is strikingly similar to the vertebrate CMZ by its peripheral location and pseudostratified nature, and shares a common pattern of slow‐cycling cells, spatial differentiation gradient, and response to postnatal ocular growth. Additionally, its proliferative activity varies considerably among squamate species, in correlation with embryonic and postnatal differences in eye size and growth. Together our data indicate that squamates possess a proliferative peripheral retina that acts as a source of progenitors to compensate, at least in part, for postnatal ocular growth. Our findings also highlight the remarkable variation in activity and location of vertebrate retinal progenitors, indicating that the currently accepted scenario of reduced CMZ activity over the course of evolution is too simplistic. Within the eye, the neural retina is responsible for perception of visual stimuli from the environment. It develops from the neural ectoderm through early optic cup stages, and forms a complex multilayered tissue lining the posterior inner surface of the eye. Adjacent to the neural retina, another structure derived from the neural ectoderm, called the ciliary body (CB), controls visual accommodation through mechanical lens adjustment and secretes the aqueous humor of the vitreous body , cooperates with central retinal progenitor cells to generate all cell types of the mature retina. The CMZ is maintained throughout adulthood in these “lower” vertebrate groups, thus producing new retinal neurons to accommodate for continuous eye growth. Importantly, however, studies investigating the peripheral retina in amniotes have suggested that both the presence and multipotency of CMZ cells have been diminished through the course of evolution from fish to mammals , which occupies a key phylogenetic position within amniotes. In particular, whereas the precise anatomy of the reptilian eye has been well described over the past decades, only one recent study directly compared the activity of the peripheral retina in squamates, by using a limited taxon sampling (two snakes and one lizard) at an uncertain adult stage  between the retina and the CB. The RCJ progenitors accumulate proliferation markers, express conserved retinal progenitor, and differentiation markers that recapitulate developmental gene expression, and respond to changes in overall body growth rate. Importantly, we further show that the proliferative activity of the RCJ is highly variable among squamate species, in correlation with postnatal variations in ocular size and growth. Altogether, this set of new results coherently and conclusively indicates that squamates possess a proliferative peripheral retina that acts as a source of progenitors to compensate, at least in part, for postnatal ocular growth.22.1Pogona vitticeps), corn snakes (Pantherophis guttatus), and green anoles (Anolis carolinensis) were obtained from our animal facility at the University of Helsinki. For embryonic stages, fertilized eggs were incubated on a moistened vermiculite substrate at 29.5°C, and embryos were removed at regular intervals after oviposition to obtain stages covering the whole postovipositional period . Embryos were staged on the basis of their external morphology according to developmental tables available for lizards and snakes .High‐resolution computed tomography (CT)‐scans of early embryonic stages of 2.3P. vitticeps, A. carolinensis, and P. guttatus were all newly obtained in this study. HL and AL in new specimens were measured anteriorly‐posteriorly from tip of the snout to the posterior end of the external auditory meatus (or posterior end of the braincase when absent in some lizard and snake species) and from the anteriormost portion of the corneal/spectacle surface to the posteriormost portion of the eyeball, respectively, as described previously , by aligning the 3D measurement tool in three orthogonal views within volume renderings of the total head.Data on head length (HL) and eye axial length (AL) were collected for 127 different squamate species covering all major lineages of squamates (see Supporting Information). Postnatal data in Figure ly Hall, , 2009. M2.4λ of the residuals, varying between 0 (phylogenetic independence) and 1 (trait evolution under Brownian motion). For intraspecies data, ordinary least squares regressions were performed in XLSTAT software . The regression slopes were initially tested for homogeneity, and then regular or phylogenetic analysis of covariance (ANCOVA) was used to assess differences in slopes and/or intercepts between groups, developmental stages, and/or species.The relationship between AL and HL in the interspecies data was analyzed with phylogenetic generalized least squares (PGLS) comparative methods in the R package “Caper” v1.0.1  was administrated twice daily (80 mg/kg body weight) for a period of 7 days by squirting the solution into the mouth. Based on previous vertebrate studies, this duration of pulse labeling is required to detect possible persistent, slow‐cycling retinal progenitors , atonal bHLH transcription factor 7 , glial fibrillary acidic protein , hes family bHLH transcription factor 1 , hes family bHLH transcription factor 5 , neurogenic differentiation 1 , neurogenic locus notch homolog protein 1 , orthodenticle homeobox 2 , paired box 6 , retinal homeobox gene 1 , or visual system homeobox 2 . Corresponding sense riboprobes were used as negative controls. After hybridization, sections were washed and incubated overnight at 4°C with anti‐DIG antibodies  conjugated with alkaline phosphatase. A staining solution containing 5‐bromo‐4‐chloro‐3‐indolyl phosphate and nitro blue tetrazolium was applied for 1–5 days to visualize hybridization. Finally, slides were mounted using Dako Faramount aqueous medium (Agilent). IHC fluorescent staining was performed as described previously  using linear levels adjustment.Eyes were dissected and opened nasally to allow for better penetration during subsequent histological processing. Samples were fixed overnight in 4% paraformaldehyde (PFA) at 4°C before dehydration although a series of alcohol solutions , paraffin embedding, and sectioning at 7 μm. In situ hybridization (ISH) on paraffin sections was performed as described previously  . A minimum number of four RCJs per species covering similar longitudinal sectioning planes of the central region of the eye  were selected for quantification. As both the size and nuclei number of the RCJ are highly variable among species in contrast to the overall range of proliferating cell number, proliferative activity was quantified based on the absolute rather than relative number of PCNA‐immunoreactive cell nuclei per RCJ. Central retina was used as a positive control tissue for PCNA IHC in species with nonproliferative RCJ.33.1n = 4), Scincoidea (n = 3), Lacertoidea (n = 1), Anguimorpha (n = 1), Iguania (n = 10), and Serpentes (n = 5). Strikingly, in most specimens tested, immunohistochemical detection of proliferating cell nuclear antigen (PCNA) proliferation marker clearly indicates cell proliferation at the peripheral retina in a region immediately adjacent to the multilayered retina . Considering the variation in relative eye size among adult lineages, we next explored the potential correlations between relative eye size and proliferative activity at the peripheral retina. As shown in Figure P. vitticeps  = 0.32; p‐value (intercept) = 0.03). Altogether, this multispecies comparison indicates for the first time that squamates, including both lizards and snakes, exhibit postnatal cell proliferation at the peripheral retina in a RCJ region between the retina and the CB. Furthermore, the major interspecies variations in RCJ proliferative activities correlate with relative eye size, suggesting the contribution of RCJ to postnatal ocular growth in squamates.In fish and amphibians, and to a lesser extent in avians, the proliferative RM persists into adulthood, thus contributing to the postnatal increase in eye size. To first assess the overall variation in adult eye size across squamates, we compiled published and newly obtained data on both head length (HL) and eye axial length (AL) for 127 lizard and snake species covering all major lineages (Supporting Information). HL was preferred to body (snout‐vent) length in our comparative studies because of the elongated body plan in snakes and some lizard species. As expected, our combined HL and AL data indicate substantial variation in adult eye size both in absolute and relative terms  < 0.028), as revealed by pairwise comparisons of species‐specific regressions using ANCOVA analysis  < 0.006), while P. guttatus and A. carolinensis show relatively similar eye size relative to HL throughout embryonic and postnatal periods  > 0.84; p‐values (intercepts) > 0.47).In most squamate taxa, like in fish, turtles, and most amphibians, growth continues throughout life at a steadily decreasing rate , while the retinal periphery remains nonlaminated and highly proliferative at early embryonic stages . At this stage, retinal differentiation has proceeded to the periphery and the proliferative RM, presumptive RCJ, and laminated retina are all apparent, thus allowing investigation of expression patterns with defined spatial resolution. Indeed, as already shown for the vertebrate CMZ, this spatial expression gradient is presumed to reflect the temporal expression sequences of stem/progenitor and differentiation markers with respect to retinal development. We thus examined, with ISH and/or IHC, the expression patterns of classical conserved markers of retinal development, including stem/progenitor, proneural, and postmitotic neuronal differentiation markers. Similar to retinal stem/progenitor cells in the developing retina of other vertebrates (Fischer & Reh, Pax6, Vsx2, Rx1, and Hes1 (mRNA levels, Figure Gfap, which is restricted to a few cells along the retinal edge of the RM (Figure Hes1 and Pax6 (Figure Hes1 are not detected in the layer of proliferating neuroblasts. Consistent with a spatial gradient of differentiation at the peripheral retina, proneural genes known to endow progenitors with a neuronal fate, including Atoh7 and Ascl1, are mainly detected in the posteriormost part of the proliferative RM (Figure Notch1, a well‐known inhibitor of proneural genes, and its downstream target Hes5 (Figure Neurod1, Otx2, and Reln (mRNA levels, Figure Neurod1 at the posteriormost part of the RM, and their expression rather stretches throughout the postmitotic laminated retina (Figure To further investigate embryonic retinal growth in squamates, and more particularly the formation and patterning of the proliferative RM and RCJ, we characterized at the molecular level the peripheral retina in elopment 0 dpo. Atelopment 0 dpo. Atelopment 0 dpo. Atelopment 0 dpo. AtM Figure . In addielopment 0 dpo. Atelopment 0 dpo. Atelopment 0 dpo. Atelopment 0 dpo. Atelopment 0 dpo. Atelopment 0 dpo. Atelopment 0 dpo. Atelopment 0 dpo. At3.4P. vitticeps. Based on the species‐dependent proliferation patterns observed at the RCJ during both embryonic and adult stages, we further hypothesized that this progenitor activity could be influenced by the overall eye growth that accompany body size increase at postnatal stages (Figures P. vitticeps, particularly in newborn and juvenile animals (0–12 months after hatchling, Figure To determine if the identified proliferative RCJ could serve as a source of retinal progenitors beyond embryonic stages, we next characterized the activity and gene expression profiles of the postnatal peripheral retina in  Figures n and 2a.P. vitticeps, we next performed BrdU pulse‐chase assays at different postnatal stages (Figure To further assess the localization and behavior of putative slow‐cycling, label‐retaining stem/progenitor cells in the peripheral retina of s Figure . As preds Figure . Finallys Figure .P. vitticeps. In addition, our data strongly suggest that this stem/progenitor zone constitutes a source for continued neurogenesis contributing to postnatal retinal growth.Altogether, these results demonstrate the existence of slow‐cycling stem/progenitor cells at the RCJ as well as the maintenance of a spatial gradient of neuronal differentiation, largely recapitulating the dynamic gene expression pattern observed during embryonic development, in the postnatal peripheral retina of 3.5P. vitticeps, the RCJ in juvenile and adult snakes is strongly reduced in both size and proliferative activity (see Figure P. guttatus indicates major differences in the expression patterns of stem/progenitor and differentiation markers at both embryonic (Figure Pax6, Figure P. guttatus is characterized by the virtual absence of progenitor markers such as SOX9 and Pax6. To further assess the proliferative activity of the peripheral retina in snakes, a BrdU pulse‐chase experiment similar to that of P. vitticeps was performed in juvenile P. guttatus (Figure P. guttatus at both embryonic and postnatal stages, and are in line with the limited postnatal growth and overall expression pattern of peripheral retina markers in this species.In contrast to c Figure a–d and pc Figure e–h stagec Figure b,f, SOX9c Figure a,e. Simis Figure k, BrdU‐p4Anolis and Gallotia. This variation in adult progenitor activity at the peripheral retina has already been noticed in other vertebrate classes such as avians, with quail having a reduced CMZ compared to chicken, thus highlighting the importance of sampling and species selection in comparative retinal studies.Following its discovery in amphibians more than 50 years ago (Hollyfield, Similarly to the situation in lizards and snakes, other populations of proliferating stem/progenitor cells anteriorly adjacent to the retina have already been observed at the peripheral retina in several amniote species Figure . In partPrevious vertebrate studies have reported that the proliferative activity of the CMZ, RM, and/or CB contributes to postnatal retinal growth and correlates with increase in ocular size, thus ensuring optimal visual perception. For example, both birds and mammals show determinate growth and reach their final eye size relatively early in their lifetime, coherent with a transient proliferative activity limited to a few weeks after birth at the peripheral margin (Ahmad et al., In conclusion, our detailed large‐scale analysis reveals for the first time that squamates contain a variable source of postnatal proliferating progenitors in a pseudostratified RCJ at the peripheral retina. Strikingly, the RCJ shares with the CMZ a common pseudostratified nature, pattern of slow‐cycling cells and progenitor markers, and response to postnatal ocular growth, suggesting that it might be a functionally equivalent structure. Our new findings also highlight the remarkable variation in activity and location of proliferative peripheral retina structures among and within vertebrate species, indicating that the currently accepted general scenario of reduced CMZ activity across evolution is too simplistic.The authors declare no potential conflict of interest.J.E. and N.D.P. designed the experimental approach and selected the species sampling. J.E., L.S., and S.M. performed all experiments and 3D image segmentation. J.E., L.S., S.M., and N.D.P. collected and prepared most of the reptile embryos. J.E. and N.D.P. prepared the figures and wrote the paper, and L.S. and S.M. contributed in the form of discussion and critical comments. All authors approved the final version of the manuscript.Supplementary Table 1 List of squamate species, measurements, and references used in the study. Species are classified by group and family names.Click here for additional data file.


Older adults with postlingual sensorineural hearing loss (SNHL) exhibit a poor prognosis that not only includes impaired auditory function but also rapid cognitive decline, especially speech-related cognition, in addition to psychosocial dysfunction and an increased risk of dementia. Consistent with this prognosis, individuals with SNHL exhibit global atrophic brain alteration as well as altered neural function and regional brain organization within the cortical substrates that underlie auditory and speech processing. Recent evidence suggests that the use of hearing aids might ameliorate this prognosis.The objective was to study the effects of a hearing aid use intervention on neurocognitive and psychosocial functioning in individuals with SNHL aged ≥55 years.All aspects of this study will be conducted at Swinburne University of Technology . We will recruit 2 groups (n=30 per group) of individuals with mild to moderate SNHL from both the community and audiology health clinics . These groups will include individuals who have worn a hearing aid for, at least, 12 months or never worn a hearing aid. All participants would be asked to complete, at 2 time points (t) including baseline (t=0) and follow-up (t=6 months), tests of hearing and psychosocial and cognitive function and attend a magnetic resonance imaging (MRI) session. The MRI session will include both structural and functional MRI (sMRI and fMRI) scans, the latter involving the performance of a novel speech processing task.This research is funded by the Barbara Dicker Brain Sciences Foundation Grants, the Australian Research Council, Alison Hennessy Audiology, and Chelsea Hearing Pty Ltd under the Industry Transformation Training Centre Scheme (ARC Project #IC140100023). We obtained the ethics approval on November 18, 2017 (Swinburne University Human Research Ethics Committee protocol number SHR Project 2017/266). The recruitment began in December 2017 and will be completed by December 2020.This is the first study to assess the effect hearing aid use has on neural, cognitive, and psychosocial factors in individuals with SNHL who have never used hearing aids. Furthermore, this study is expected to clarify the relationships among altered brain structure and function, psychosocial factors, and cognition in response to the hearing aid use.Australian New Zealand Clinical Trials Registry: ACTRN12617001616369; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617001616369 (Accessed by WebCite at http://www.webcitation.org/70yatZ9ze)RR1-10.2196/9916 Aging is associated with the onset of postlingual sensorineural hearing loss (SNHL), which refers to hearing loss (or deafness) arising from the pathology of either the inner ear organs or the vestibulocochlear nerve after language acquisition. SNHL accounts for approximately 90% of hearing loss cases in adults and is insidious, progressing from normal (pure tone average [PTA]=0-25 dB) to mild PTA=26-40 dB), to moderate PTA=41-70dB), to severe (PTA=71-90 dB), and ending with profound (PTA >91 dB) or total hearing loss. However, more alarming are the sequelae of SNHL that might include rapid cognitive decline -70dB, to, and inc0 dB, to The scale of these problems is brought into sharp focus in the light of SNHL being the most prevalent chronic condition affecting older adults in developed countries 16%-20%) -10 and t%-20% -10The mechanisms underlying the links among cognitive decline, dementia risk, and SNHL are unknown but have been proposed to be due to either common neurodegenerative causes ,18 or doThe initial stages of speech processing in normal hearing adults involve the analysis of basic speech sounds, including phoneme  and acoustic processing , which oTypically, individuals with SNHL adapt to their altered aural predisposition by relying increasingly on visual cues, including lip-reading. In normal hearing older adults, lip and word reading broadly activate the dorsal articulatory and spectrotemporal and phonological analysis networks mentioned above, except the primary auditory cortices due to the diminished auditory function . FurtherThis functional alteration is thought to stem from the loosening of associations between memory and phonological processes and viseme  processes as SNHL progresses   is utilized in combination with clinical, neuropsychological, and hearing tests, aims to investigate the neurocognitive and psychosocial effects of wearing hearing aids in older adults with SNHL (ACTRN12617001616369).Through this study, we seek to understand whether the use of hearing aids can alter the neurocognitive function and affect beneficial plastic brain changes in individuals with SNHL. In particular, we aim to determine whether early intervention can normalize the function of the speech processing brain network. To this end, we will use neuropsychological, clinical, and psychophysical tests in combination with functional and structural MRI (fMRI and sMRI). In addition, fMRI acquisitions will include scanning during the performance of a speech processing task (detailed later) to probe the function of the speech processing network, besides the resting state fMRI to probe the brain network function more generally, whereas sMRI would enable the assessment of both the volume and integrity of the gray and white matter.In comparison to the long-term hearing aid users, after wearing a hearing aid for 6 months, the group who have never worn a hearing aid will exhibit improved cognition, reduced depression, improved social interaction, altered activation of the auditory cortices and attendant networks, and altered connectivity between auditory and attendant networks.In addition, the study will explore any baseline relationships among the cognition, psychosocial, and neural function in participants with and without a hearing aid and any relationships among the improved cognition, psychosocial function, and neural function in participants without a hearing aid after the hearing aid intervention, as seen in The study is a prospective cohort design evaluating the effect of the hearing aid use on cognition, psychosocial factors , and neural function. We will recruit 2 participant groups of similar size consisting of people with mild to moderate SNHL. Of note, group randomization is not possible in this study; however, the groups will be matched as much as possible in terms of the degree of hearing loss.Group A: Patients with SNHL who have used hearing aids for, at least, the previous 12 months and plan to continue using their hearing aids for the next 6 months.Group B: Patients with SNHL who have never used hearing aids before and who will be willing to wear hearing aids for the next 6 months.All participants would be asked to complete, at 2 time points (t) including baseline (t=0) and follow-up (t=6 months), tests of hearing and psychosocial and cognitive function and attend an MRI session.Participants must be aged 55-90 years, speak English as first language, exhibit mild or moderate SNHL with a PTA of thresholds at 0.5-4 kHz in both ears, willing to undergo two 1-hour MRI scanning sessions over a period of 6 months, and willing to wear hearing aids for 6 months or must have been wearing hearing aids for at least 1 year. Furthermore, participants must give written informed consent.Participants will be excluded if they exhibit left handedness, marked visual impairment that would prevent reading, cognitive impairment , severe or profound hearing loss, and MRI contraindications. Audiology health clinics with existing relationships with the Swinburne University, such as Alison Hennessy Audiology and Chelsea Hearing Pty Ltd, will be contacted to distribute the study promotional material to their clients who have previously undergone hearing assessments at the audiology clinic, been diagnosed with mild or moderate SNHL, and have been wearing their hearing aids for at least 1 year. In addition, the clinic will distribute promotional materials to clients who have recently been recommended to acquire hearing aids but have not yet decided to purchase the aids. All clients who express interest in the study through the audiology clinic will be invited to attend an information session at the Swinburne University of Technology.Participants who live within the Swinburne community will also be contacted by telephone and email by the researchers to explain the study; participants who express interest will be invited to attend the information session at Swinburne University. At the information session, the researchers will explain the purpose and significance of the study. At the same time, participants will complete a screening questionnaire to identify participants who will be willing to undergo hearing assessments, undergo two 1-hour MRI scans, and fulfill the inclusion criteria. Before completing the screening questionnaire, participants must provide verbal consent. Then, selected participants will be provided with a participant information and consent package for review, which will include further detailed information on the study procedure and a consent form. Participants willing to participate in the study will be scheduled for hearing assessment at the audiology clinics. At the hearing appointments, participants will submit their written consent before their hearing assessments, and those who meet the inclusion criteria will be scheduled to undergo their first MRI scan at a mutually convenient time at the Swinburne University of Technology.d=0.63 for between-group differences. Allowing 10% attrition in the 6-month follow-up period, a sample size of 27 in each group with a significance level of 5% and power of 80%, a significant group-by-time interaction effect can be detected for a large effect size of d=0.77. This study is based on the assumption that an effect size of dWith 30 consented participants in each group with a significance level of 5%, the power of 80%, and controlling for age, gender, and level of education, the baseline analysis of covariance (ANCOVA) model for spatial working memory performance can detect effect sizes of Group B participants will be fitted with two demonstration hearing aids, known as Unitron Tempus Moxi Fit Receiver-in-the-ear hearing aids . The hearing aids will be fitted by professional audiologists at the participating audiology clinics according to the best practice fitting guidelines including real ear (probe tube) measures to verify the amplification and match the appropriate prescribed amplification  with fuDuring the 6-month waiting period between MRI scans, phone call and email reminders for the second testing session will be sent to all participants at 1, 3, and 5 months. At the same time, counseling and other compliance-improving policies -46 will All participants will return to the audiology clinics for further hearing assessments. Group B participants who received loaned hearing aids will return them. In addition, hearing aid supplier information will be provided to them if they are ready to purchase hearing aids. After hearing assessments, participants will return to the Swinburne University to complete the 6-month follow-up assessments.Participants who decide to withdraw because of some discomfort experienced with hearing aids or do not undergo a second MRI testing will be retained in the study for baseline MRI analyses only. In addition, intention-to-treat (ITT) analyses will be used for other analyses not involving MRI data.No costs would be associated with participating in this research project other than transport costs. All participants will be reimbursed Aus $60 to cover these costs after the completion of the 6-month testing protocol.The assessments selected in this study are categorized as follows: hearing assessments, demographic questionnaire, hearing aid benefit questionnaire, cognitive performance, mood and social interaction assessments, and MRI scanning. All participants enrolled in this study will complete these assessments at the baseline and again after 6 months.Otoscopy and TympanometryFollowing otoscopy, all participants will undergo tympanometry and acoustic reflex testing to assess the status of the middle ear ,48.To understand the degree of hearing impairment, and classify participants according to the type of hearing loss, hearing ability will be measured at threshold frequencies of 0.25, 0.5, 1, 1.5, 2, 3, 6, and 8 kHz (air conduction) and 0.5, 1, 2, and 4 kHz (bone conduction) in both ears. The choice of frequency to be tested corresponds to the amplification range of most modern hearing aids and is consistent with the capturing sensitivity at frequencies affected by SNHL and noise-induced damage. Only participants with either mild or moderate SNHL will be included in this study ,48.Data on a variety of demographic variables will be collected to describe the characteristics of study participants.The Abbreviated Profile of Hearing Aid Benefit (APHAB) inventory , which iThe APHAB inventory subscales exhibit acceptable reliability with Cronbach alpha value of .87 (EC), .83 (RV), .82 (BN), and .86 (AV) in unaided conditions, and test-retest correlation coefficients of .80, .65, .71, and .89, respectively .MMSE will be used to assess cognition and will be administered to test the cognitive functioning. MMSE is a valid and reliable way of globally assessing a limited range of cognitive functions . This exThe Swinburne University Computerized Assessment Battery (SUCCAB) will be used to assess the cognitive performance. This cognitive test battery will allow the assessment of changes in the cognitive performance of all participants over a period of 6 months. The battery will test contextual memory, immediate recognition, simple reaction time, choice reaction time, congruent stroop, incongruent stroop, spatial working memory, and delayed recognition memory. The reliability and validity testing of this battery has demonstrated that SUCCAB is sensitive to aging and has been shown to be particularly effective for measuring short-term changes in cognition of the elderly . FurtherDepression, Anxiety, and Stress Scale (DASS) is a well-established self-rating mood scale for measuring 3 related negative emotional states of depression, anxiety, and stress. To assess changes in mood in this study, DASS-21, which is a shortened version (21 items) of the full DASS (42 items), will be used . DASS-21The Berkman-Syme Social Network Index (SNI)  will be matched (MAT), mismatched (MIS), no sound (NOS), and control (CON), preceded and followed by 10-second rest periods, where a fixation cross (“+”) will be displayed. In each of 2 scanning runs, 4 repetitions of each block type  will be presented in a pseudorandom order, each utilizing different word stimuli. The stimulus presentation time for each of the two scanning runs will be 426 seconds (7 minutes 6 seconds); an additional 20 seconds of imaging data will be acquired following the end of the stimulus presentation to allow the hemodynamic response to return to the baseline.During fMRI scanning, participants will view a series of human faces  that mouth words in blocks (or “epochs”) lasting 16 seconds (1 word per 2 seconds) each. Each block will be one of 4 conditions termed During MAT, the faces will mouth single syllable, high-frequency words , such as “cat” or “house,” and the corresponding audio input (auditory stimuli) will be played through the headphones. During MIS, the stimuli will remain the same, but the mouthed words and auditory stimuli will be semantically unrelated . During NOS, the visual stimuli will be presented but not the auditory stimuli. During CON, the faces will be presented but will not mouth the words; instead, they will simply open and close the mouth without auditory stimuli. All participants will be asked to press a button whenever a face appears to ensure participant attendance to the task.The MRI scanning session will include the acquisition of 4 different types of scan data while participants lie supine in the scanner wearing MRI-compatible OptoActive headphones (OptoAcoustics). Participants will have either normal or corrected to normal vision using MRI-compatible goggles. These acquisitions will include 2 fMRI scanning runs while participants perform the speech processing task, a high-resolution T1-weighted structural image (∼8 minutes), diffusion-weighted images (∼10 minutes), and a resting state fMRI scanning acquisition (∼10 minutes); the total scanning time will be 42 minutes.The following details the different scan protocols, including scan parameters, preprocessing, and data analysis:3 isotropic voxels). Preprocessing and statistical analysis will be performed using SPM12 and associated toolboxes. Preprocessing will include slice-timing correction, motion correction, coregistration of realigned functional images to structural (T1-weighted) scans, warping  of structural and functional scans into standardized stereotactic space, and spatial smoothing of functional images. The data will be modeled by constructing separate regressors that depict the onset and duration of MAT, MIS, NOS, and CON blocks, convolved with the canonical hemodynamic response function supplied with SPM12. Covariates of no interest  will model noise components.Scan acquisition for the speech processing task will utilize a T2* sensitive echo-planar imaging sequence . In addition, multiband acquisition sequences will be derived from the Human Connectome Project . Data an3 voxels). Diffusion-weighted images will be acquired using an isotropic diffusion tensor imaging sequence for fractional anisotropy (FA) estimations . In addition, T1-weighted images will be used in the coregistration of functional data and also perform the analysis of regional brain volumes using voxel-based morphometry (VBM) using DARTEL procedures. For VBM, images will be manually reoriented and segmented [The T1-weighted image will be acquired using a magnetization-prepared gradient echo sequence  white matter tractography using “MRTrix”  to assesAs the speech processing task will involve hearing word stimuli, the auditory input for each participant will be tailored to fit a normalized audiogram, that is, the gain will be enhanced at impaired frequencies. This will be performed by fitting a spline function to prerecorded audiograms that will be used to modulate auditory stimuli for the left and right ears separately. Additionally, the headphone output will be modified such that it is consistent across individuals.In this study, repeated measures mixed model group (no hearing aid vs hearing aid users) x Time (Time 1 vs Time 2) analysis (RMMM) will be used for all analyses. The missing data will be accommodated in this analysis; however, in the case of whole-brain fMRI analyses, only completed protocol participants will be included. In the ITT RMMM analyses, the autoregressive (AR) dependence will be assumed.The SUCCAB performance measure for spatial working memory will be used as the primary SUCCAB measure; this measure has been found to be particularly effective in measuring short-term changes in cognition of the elderly  and is cMood and Social Interaction DataIn this study, the mood will be assessed using the DASS scale, and social interaction will be measured using the Berkman-Syme SNI. The baseline measures for the 2 groups will be compared using analysis of variance. In addition, changes in these measures over time will be compared for the 2 groups of respondents using an ITT RMMM, controlling for age, gender, and education level and any variable that differs markedly between the groups at the baseline.Neuroimaging DataInferences from functional and structural neuroimaging analyses will be assessed using the random field theory to correct for multiple comparisons at the cluster level.First, we will compute the contrast of MAT>NOS (NOS controls for viseme processing) for each participant and enter the contrasts into an RMMM to assess the effect of the first-time hearing aid use on speech sound processing; (2) we will assess changes in the functional connectivity in key areas determined from this analysis using the generalized psychophysiological analytic approach ; (3) finSecondly, we will compute the contrast of NOS>CON (CON controls for basic face motion processing) for each participant and enter the contrasts into an RMMM to assess the effect of the hearing aid use on viseme processing; (2) we will assess changes in the functional connectivity in key areas determined from this analysis using the generalized psychophysiological analytic approach ; (3) finTo assess plastic alteration in response to the first-time hearing aid use, these spatially smooth gray matter images will be entered into an RMMM.Correlations between the SUCCAB performance measures and neuroimaging data will be investigated at the baseline and after 6 months for each o group using ANCOVA analyses and ITT Hierarchical Linear Model analyses.Correlations between DASS and the Berkman-Syme SNI with the SUCCAB performance measures and the neuroimaging data will be investigated at the baseline and after 6 months for each group using ANCOVA analyses and ITT Hierarchical Linear Model analyses. In addition, structural equation modeling will be used to explore the role of the mood and social interaction data as process variables for the effects of hearing aid use on the cognition and neural function, testing the hypothesized model shown in We will explore changes in phoneme and viseme processing separately and their integration, as a function of the hearing aid use by modeling combinations of MAT, MIS, NOS, and CON, in addition to any change in the functional connectivity using the generalized psychophysiological analytic approach . In addiThe speech processing task was programmed and tested during September 2017-December 2017. Training of research staff on research protocols  was conducted intermittently between February 2016 and February 2020. In addition, the baseline testing sessions will commence in February 2018 and will be completed by June 2020, and the follow-up sessions will be completed by December 2020. Furthermore, baseline session data analyses will be completed by October 2019, and final longitudinal data analyses will be completed by July 2020.SNHL is strongly associated with cognitive decline, social and mental health problems, and incident dementia. SNHL leads to brain atrophy and neuroplasticity that may be detrimental to auditory rehabilitation. Some evidence indicates that the use of hearing aids may slow or improve this pathology. In this retrospective cohort study, we utilize cognition and psychosocial testing in combination with structural and functional neuroimaging to assess the impact of the hearing aid use on the neurocognitive function and brain structure in those with SNHL. To the best of our knowledge, this is the first study to directly assess structural and functional brain changes arising from the use of hearing aids in older adults with SNHL. Currently, there is a paucity of neuroimaging studies in the SNHL field generally, which is surprising given what is known about neural plasticity in SNHL. A chief motivation for this work is to address this shortcoming, yielding critical data for SNHL research and ideally, may prompt greater use of hearing aids in those with SNHL.This study has some limitations that must be addressed. There are numerous aspects of speech processing, in general, and its impairment in SNHL. In this study, we have chosen to examine the processing of one aspect alone, namely monosyllabic word processing. This approach was selected to make the task easy to perform for participants and to ease data interpretation. Hence, our analyses will not reveal all aspects of speech processing dysfunction in SNHL such as sentence comprehension . In addiSNHL is a major and growing health problem for older adults that touches most aspects of their lives, especially their cognitive function, mental health, and well-being. The use of hearing aids enhances the lives of these individuals through not only enhanced hearing but also improved social interaction, mood, and cognitive functioning. Such day-to-day functional enhancement in individuals with SNHL suggests that beneficial plastic changes occur in their brains as a consequence of hearing aid use; however, the use of hearing aids among this population is low.


Assessments of standardized region/population-specific audiological characteristics are needed for provision of effective rehabilitative services through reducing costs associated with hearing aids. This study aims to propose a set of standard audiograms representing the Korean population that were derived by analyzing data from the 2009–2012 Korea National Health and Nutrition Examination Survey (KNHANES), a nationwide epidemiologic study conducted by Korean government organizations. Standard audiograms were derived by applying a hierarchical clustering method from recorded audiologic data that were obtained independently at 6 frequencies for each ear: 0.5, 1.0, 2.0, 3.0, 4.0, and 6.0 kHz (in dB HL). To derive the optimal number of clusters of the desired standard audiograms, cubic clustering criterion, pseudo-F-, and pseudo-t2-statistics were calculated. These analyses resulted in 29 clusters representing a standard audiogram of the South Korean population. Eighteen of the clusters represented normal hearing audiograms (73.11%), while 11 represented hearing-impaired (HI) standard audiograms (27.89%). Of the 11 HI audiograms, 7 were defined as flat-type (17.81%), while the remaining 4 were defined as sloping-type (9.08%). In conclusion, 29 audiograms representing standard audiograms for the Korean population have been derived using KNHANES data. Improved understanding of the characteristics of each cluster may be helpful for development of more personalized, fixed-setting hearing aids. According to region, South Asia has the highest prevalence (27%) and the Middle East and North America the lowest (3%). Some low-income regions have twice the prevalence of hearing loss of high-income regions (11%). Population origin/ethnicity also plays a role in the prevalence of hearing loss2.According to the World Health Organization (WHO), as of 2012, there were 360 million people in the world with hearing loss, with prevalence depending on sex, age, income, and region4. Hearing aid ownership is the lowest among socioeconomically disadvantaged groups, including ethnic minorities and those with the lowest levels of income and education5. Currently, hearing aids are fitted by experienced health care professionals, and this fitting procedure increases the price of hearing aids. Self-fitting hearing aids, personal sound amplification products (PSAP), or devices with several fixed fitting modes are now available to reduce costs. Simple, useful amplification formulae are necessary for these devices to be used universally.Despite the growing number of people with hearing impairment, the hearing aid adoption rate is staggeringly low, at only 1 in 5 hearing-impaired people. There are several reasons for this low adoption rate, but one of the main reasons is the high cost of the devicesBefore providing formalized amplification formulas, it may be beneficial to address the nature of “standard audiograms.” The use of standard audiograms for hearing aid design was first suggested by the Nordic Cooperation on Disability (NSH) in 2003, during discussions about modernizing hearing aid measurement standards. The proposed sets of audiograms are intended to be used for hearing aid measurements in which the effects of fitting or the use of certain features, such as wireless streaming technology or noise reduction technology, must be demonstrated objectively. This information would be used to generate data and instruction for use on hearing aids, hearing aid features, and fitting methods.6. However, the proposed audiograms accounted only for 26% of patients when checked against a database of 15,000 standard audiograms from the Stockholm South Hospital. In 2010, the International Standards for Measuring Advanced Digital Hearing Aids (ISMADHA) group proposed a set of 10 standard audiograms using a statistical approach that applied to 46% of the 28,244 audiograms used in the study6. In the context of such variation, it could be beneficial to provide standard audiograms representing region/population-specific hearing loss trends. Assessment of standardized region/population-specific audiological characteristics is needed by healthcare providers seeking to create effective rehabilitative services7. To our knowledge, there are no studies of hearing impairment trends in East Asia, and standard audiograms based on data from nationwide epidemiologic studies set in East Asia are lacking.Several studies have established standardized audiograms. In 2003, the NSH first proposed a set of five audiograms, representing (1) mild sensorineural loss, (2) moderate sensorineural loss, (3) severe sensorineural loss, (4) profound sensorineural loss, and (5) precipitous sensorineural loss, purely based on their experienceThis study aims to propose a set of standard audiograms representing Koreans generated through hierarchical clustering analysis of data from the 2009–2012 Korea National Health and Nutrition Examination Survey (KNHANES), a nationwide epidemiologic study conducted by Korean government organizations.The study used a statistical approach to create standardized audiograms through hierarchical clustering analysis to represent trends of hearing loss in the South Korean population. Written informed consent was obtained from all participants before the survey, and approval for this research was obtained from the Institutional Review Board of Samsung Medical Center (IRB No. 2013-02-031).10. In the KNHANES, a field survey team consisting of an otolaryngologist and nurse performs interviews and physical examinations. Selected participants undergo basic otolaryngologic examinations. A history of otological symptoms is surveyed, and physical examinations including the tympanic membrane, hearing, and balance along with pure tone audiometry are conducted in participants of appropriate ages. Every year, 10,000–12,000 people in approximately 3,800 households are selected from a panel to represent the Korean population using a multistage clustered and stratified random sampling method based on Korean National Census Data. From the chosen data set, 192 survey sections and 20 households were selected from each section. The participation rates for the medical examinations were high: 79.2%, 77.5%, 76.1%, and 75.9% for 2009–2012, respectively.KNHANES is a nationwide survey that is performed annually by the Korea Centers for Disease Control and Prevention to analyze the health and nutritional statuses of a representative Korean population sample. This survey is a cross-sectional survey of the civilian population aged ≥1 year living in households in South Korea and is described in detail elsewherePure tone audiograms were measured by a trained otolaryngologist using an automatic audiometer  in a soundproof booth. Pure tone thresholds were obtained independently at 6 frequencies for each ear: 0.5, 1.0, 2.0, 3.0, 4.0, and 6.0 kHz. The pure-tone average (PTA) was obtained as the average threshold at 0.5, 1.0, 2.0, and 4.0 kHz. To ensure reliability, the Epidemiologic Survey Committee of the Korean Society of Otorhinolaryngology-Head and Neck Surgery periodically organized seminars for otolaryngologists as a means of quality control.11. Using sample weight, this survey provided representative estimates of the Korean civilian population living in households. Audiogram data  were obtained from the 2009–2012 KNHANES. Such data can be powerful tools for investigating the national prevalences of specific diseases and health behaviors. KNHANES data were used to produce a standard audiogram to comprehensively represent hearing impairment trends in Korea.Pure tone audiograms were conducted in participants aged 12 years or older who were eligible for the survey. Out of the 34,251 participants who took part in the 2009–2012 KNHANES, 18,415 (≥12 years) underwent medical examinations including pure tone audiometry. Audiograms from 36,828 ears were selected after excluding missing and erroneous measurements. Each individual participant represented the Korean population at a different weight calculated by the sampling rate, response rate, and age/sex proportions of the reference population12, pseudo-F-, and pseudo-t2-statistic13 were calculated. The CCC can be used to estimate the number of clusters using Ward’s minimum variance method, k-means, or other methods based on minimized within-cluster sum of squares. Statistical analyses were executed using SAS version 9.4 .Standard audiograms were obtained by applying a hierarchical clustering method to derive new standard audiograms from the total data set of recorded audiograms showing hearing thresholds (dB HL) at six frequencies of 500, 1,000, 2,000, 3,000, 4,000, and 6,000 Hz. Hierarchical clustering is a method of cluster analysis that seeks to build a hierarchy of clusters. To derive the optimal number of clusters of desired standard audiograms, cubic clustering criterion (CCC)The suggested audiograms were categorized into two groups according to PTA: 1) normal hearing (NH) audiogram if the PTA was below 25 dB and 2) hearing-impaired (HI) audiogram if the PTA was equal to or greater than 25 dB. If the difference between two adjacent frequencies was equal to or greater than 20 dB, they were defined as steeply sloping losses.The statistical method resulted in 29 clusters representing the standard audiogram of Korea. Figure Of the 11 HI audiograms, 7 can be defined as flat-type, (17.81%), and 4 can be defined as sloping-type (9.08%) Fig. . Sex andIn contrast to the flat-type HI audiograms, the peak age band of the sloping type HI audiogram lies in the 41–60 year range except for cluster 16, which represents gradual hearing loss with a steep change between 1000 and 2000 Hz. Clusters 27, 28, and 29 show normal hearing thresholds below the frequency of steep change .et al.2).This is the first study to propose standard audiograms based on nationwide epidemiologic study data. The present study is based on the 2009–2012 KNHANES, which provides powerful tools for investigating the national prevalences of specific diseases and health behaviors. The 29 proposed standard audiograms represent the national HL trends of South Korea, rather than encompassing only a city and its surrounding suburbs. Moreover, since only ethnically Korean individuals participated in the KNHANES, the proposed standard audiograms are valuable to compare HL trends between populations, especially since there are abundant data regarding the hearing trends of Europeans, African-Americans, and Hispanics  hearing aids. Expert intervention during the hearing aid fitting process is reduced with the use of these devices, and self-fitting will be more widely performed in the future. Standard audiograms are beneficial to help develop formalized amplifications for self-fitting, which can be operationalized as preset modes. Such features reduce the cost of hearing rehabilitation and are helpful for improving the experience when people with hearing loss begin to use PSAP or OTC hearing aids. The present study results provide a range of seven flat and four sloping audiograms that are applicable to hearing-impaired populations in Korea. Identifying representative audiograms is helpful to produce standardized products such as PSAPs or basic HAs to provide users with more personalized, fixed settings. Fixed settings that are appropriate for different regions or ethnicities and that are based on standard audiograms offer much higher likelihood of achieving optimal fit using fixed settings provided for a reasonable price.This study has some limitations. Although the clustering analysis incorporated a large set of nationwide data, and the results may be referred to as standard audiograms, causal or associated factors of hearing loss were not evaluated, and it is difficult to explain the characteristics of each standard audiogram. This may restrict the understanding and use of standard audiograms. Second, while the pure tone audiograms were measured by a trained otolaryngologist with an automatic audiometer, bone-conduction hearing thresholds were not determined. If bone-conduction hearing thresholds were available, those data may be helpful to suggest more optimal treatments for each patient group. However, hearing thresholds obtained from subjects with normal tympanic membranes were used in this study, and this could minimize the bias through which conductive hearing loss affects clustering outcomes.Twenty-nine audiograms representing the population of South Korea were proposed using KNHANES data. This is the first study to propose standard audiograms based on nationwide epidemiologic study data. The results suggest 18 clusters representing normal hearing trends and 11 clusters representing hearing loss trends in South Korea. A greater understanding of the characteristics of each cluster would be helpful for development of more personalized fixed-setting HAs such as PSAPs or basic HAs. These would lower costs and make HAs accessible to more users.


BackgroundHearing impairment is found to be the most prevalent disabling condition worldwide. Early diagnosis is crucial to avoid speech and language delays and to ensure the best performance results after cochlear implant (CI) surgery. Universal newborn hearing screening is a way to recognize newborns with a hearing impairment with or without risk factors. In this article, we have studied the effect of the newborn hearing screening program on early presentation to a healthcare center and, hence, early intervention in patients with congenital hearing loss, and reviewed the international numbers.ObjectivesThe objective of this study was to determine whether neonatal hearing screening in Saudi Arabia helped prelingually deaf children to present earlier or not.DesignRetrospective cross-sectional reviewSettingKing Abdullah Ear Specialist Center (KAESC), Riyadh, Saudi ArabiaSubjects and methodsWe included all patients who presented to the CI committee for the first time at KAESC, between March 2016 and March 2018, and met the inclusion criteria. Data were retrieved through phone calls and patient files. The sample size was 242.Main outcomesThe timing difference between those who were screened positive for hearing loss at birth versus patients who were screened negative or not screened at all.ResultsBy far, patients who were screened positive for hearing loss presented earlier  to a healthcare center than those who were not screened at all or screened negative for hearing loss and they finished the journey to CI 17 months earlier than those who were not screened. On the other hand, those who were screened negative were not found to present later than those who were not screened.ConclusionGoing with the international trend, screening was found to have a significant positive effect on age at presentation, diagnosis, hearing aid fitting, surgery, and, hence, performance after implantation. Testing false negative on screening did not show a significant further delay when compared to those who were not screened. Hearing impairment is considered the most prevalent disabling condition worldwide . AccordiAim of the studyIn the present study, we evaluated children with and without neonatal hearing screening in Saudi Arabia and determined the mean ages at the time of the following events: suspicion of hearing loss, presentation to the hospital for audiological evaluation, diagnosis, hearing aid fitting, and presentation to the cochlear implant (CI) committee. We also evaluated if patients with congenital hearing loss who showed negative results in initial screening tests, which could be due to false-positive aABR test findings or auditory neuropathy patients who were screened with OAE, presented later than those who were not screened at all. Finally, we aimed to gather a better understanding of the potential causes of delays in audiological testing and intervention in all evaluated children.Study design and settingThis study was a retrospective cross-sectional study, which was conducted at a tertiary hospital  at King Abdulaziz University Hospital) in Riyadh, Saudi Arabia.Study participantsInclusion CriteriaAll pediatric patients (up to the age of 18 years) with bilateral severe to profound hearing loss and prelingual deafness who presented to the CI committee for the first time.Exclusion CriteriaAll adult patients who presented for second ear CI, patients with post-lingual deafness, patients with acquired hearing loss, and any patients with a psychological or neurological condition.Sample SizeThe sample size of this study was 242 patients who fulfilled our inclusion and exclusion criteria.Sampling TechniqueThe participants were recruited using convenient sampling. We included all patients who presented to the CI committee for the first time at KAESC, between March 2016 and March 2018.Data collection methods, instruments used, and measurementsEach patient with a sensorineural hearing loss who has been referred to the CI committee at KAESC gets registered and undergoes a clinical evaluation and different investigations, which are all kept in an electronic file in KAESC’s registry. The patients were recruited from the CI committee registry and then our inclusion and exclusion criteria were applied. The data were collected using a self-designed data collection sheet, which consisted of two subdivisions: the first one examined the socio-demographic characteristics of the participants  while the second part examined the ages of the patients by months at suspicion of hearing loss, diagnosis, hearing aid fitting, presentation to the CI committee and whether the patient was screened at birth or not. Data were collected using phone calls with parents or a direct caregiver (for those whose parents are deceased) and patient files. The data were then transferred to an Excel sheet. Patients who were screened positive for hearing loss at birth were compared with patients who were screened negative at birth for hearing loss or those who were not screened at all in terms of age (months) at suspicion, first audiological testing, a confirmed diagnosis, magnification, and presentation to the CI committee.Data management and analysisStatistical tests were carried out using Statistical Package for the Social Science (SPSS) software . The analysis of variance (ANOVA) test was used to compare the study groups. The post-hoc test was applied to compare the groups with each other. A p-value of less than 0.05 was considered significant.Ethical considerationThe research received institutional review board (IRB) approval at King Saud University Medical City (KSUMC). Confidentiality was maintained. The research was fully explained to the patient's relatives, and verbal informed consent was obtained from them during the phone call. Patient relatives were informed that they were free to withdraw at any time and that would not affect their clinical treatment.Among the 242 patients, only 23 (9.5%) were screened positive for hearing loss at the neonatal hearing screening (did not pass the hearing screening) while 37 15.3%) were screened negative at the newborn hearing screening (passing the hearing screening ) and 182 (75.2%) were not screened at birth. The mean ages (months) at the time of the following events for the overall cohort are shown in Figure 5.3% wereThe mean ages at the same checkpoints for the three individual groups are shown in Table The ANOVA test revealed significant differences in all mean ages among the three groups . Therefore, the post-hoc test was done to compare them with each other. The results are shown in Table As shown in Table When comparing patients who were screened negative and those who not screened at birth, patients with negative screening findings and those who were not screened were suspected by their families to have a hearing loss at the mean ages of 14.5 and 15.2 months, respectively; thus, there was no significant difference between the two groups. The first audiological test in the negative screening group was performed 2.5 months earlier (mean age: 17.9 months) than that in the no screening group; this difference was also not significant. In the negative screening group, the diagnosis was confirmed at a mean age of 18.8 months, hearing aids were fitted at a mean age of 24.5 months, and presentation to the CI committee was at a mean age of 27.6 months. These values were 12.3,39.4, and 37.2 months, respectively, for the no screening group, with no significant differences between the two groups.Severe to profound hearing loss children who undergo newborn hearing screening at birth are much more likely to be diagnosed and treated in a timely manner. Newborn hearing screening programs aim to lower the ages at the time of audiological testing and intervention for children with hearing impairment. Early detection and intervention for prelingual bilateral severe to profound hearing loss are expected to minimize delays in language development. Several nations have begun implementing early identification and interventions for hearing loss and are conducting regional UNHS programs. In a study conducted in Champagne-Ardenne, hearing impairment was diagnosed at an average age of 3.2 months, and confirmation of the initial diagnosis in most children was facilitated by follow-up auditory examinations . The autIn the present study, hearing loss was suspected much earlier in children who showed positive findings for hearing loss in newborn hearing screening than children who passed the screening test  and children who were not screened at birth. As a result, the mean ages at the first audiological test, diagnosis, and hearing aid fitting were much lower for children with positive findings than for those with negative findings and those without screening. On the other hand, children with negative screening findings and those without screening showed no significant differences with regard to the mean ages at the suspicion of hearing loss, first audiological test, diagnosis, hearing aid fitting, and presentation to the CI committee. These findings suggest that even though families of children with hearing loss who passed the screening test were reassured that their children are hearing, they did not present later than those who were not screened at all.We also observed significant delays in audiological testing and hearing aid fitting in children with positive screening findings at birth. While audiological testing was performed 1.7 months later than the age of three months recommended by the Joint Committee on Infant Hearing (JCIH) 2007, hearing aids were fitted around 10.1 months later than the recommended age (within one month after diagnosis) . Since aA study conducted in Taiwan showed that UNHS helps in the early detection, diagnosis, and treatment of congenital hearing loss . In thatConsistent with international trends, the findings of our study in Saudi Arabia showed that children with severe to profound hearing loss who undergo newborn hearing screening at birth are significantly more likely to be diagnosed and treated in a timely manner. However, negative screening findings due to reasons such as false-positive ABR test findings and auditory neuropathy (in patients who were screened with only OAE) can have the same effects as a complete lack of screening. Further studies, including larger sample sizes and different speech tests, are necessary to understand the effects of UNHS on CI performance.


In patients suffering from Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) disease severity is assessed by Medical Research Counsil (MRC) Scale or Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. However, none of these methods is appropriate to objectively assess muscle weakness or to detect very small subclinical changes. More objective and quantitative measures are needed in order to evaluate treatment efficiency or to detect subclinical affection of upper limps for early diagnosis. The goal of our study was to objectively quantify muscular weakness in CIDP patients with the non-invasive Quantitative Motor (Q-Motor) test of Grip Force Assessment (QGFA) as well as the Involuntary Movement Assessment (QIMA) and to search for differences between typical and atypical CIDP variants. In addition, we hypothesized that Q-Motor findings correlate with disease severity scales such as MRC or INCAT score.In this cross-sectional exploratory proof-of-concept study subjects with confirmed diagnosis of typical or atypical CIDP were examined and compared to healthy controls (HC). For Q-Motor tests all subjects had to lift a device (250 g and 500 g) equipped with an electromagnetic sensor that measured grip force (GF) and three-dimensional changes in position and orientation. The measures “grip force variability” (GFV), “position index” (PI) and “orientation index” (OI) were provided to assess involuntary movements due to muscular weakness.33 patients with CIDP and 28 HC were included. All measures were significantly elevated in CIDP patients for both devices in the right and left hand compared to healthy controls. Subgroup analysis revealed no differences between typical and atypical CIDP variants. INCAT score only weakly correlated with OI and PI. However, there was a stronger correlation between MRC and QIMA parameters in both hands.Q-Motor assessments were capable to objectively assess muscular weakness in CIDP. In particular, QIMA measures detected subclinical generalized muscle weakness even in patients with milder disability. Sensitivity and rater-independence of Q-Motor assessments support a further exploration of QIMA measures as potential endpoints for future clinical trials in CIDP. Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare autoimmune disorder of the peripheral nervous system leading to both proximal and distal weakness of all extremities. Beside this typical manifestation, there is a proportion of patients suffering from atypical variants such as pure sensory (sensory CIDP), distally acquired demyelinating polyneuropathy (DADS) or asymmetric multifocal acquired demyelinating sensory and motor polyneuropathy (MADSAM) neuropathies , 2. CIDPMedical Research Council Sum Score is often applied in order to measure the muscle strength on the level of impairment ) as well as patients with higher arm function disability  showed significantly higher values for the PI as well as for OI for both hands and weights compared to HC. For grip force variability, only patients with INCAT-A ≥ 2 showed significant increased values compared to HC  as well as for orientation index (OI)  but not with MRC (data not shown). OI of both hands correlated by trend with INCAT . There was also a moderate correlation of OI with MRC-A of both hands for 500 g  and for the right hand with 250 g . There was no correlation of PI with INCAT or INCAT-A (data not shown). However, we found a moderate correlation of PI with MRC-A for the both hands .For all parameters that were significantly increased in CIDP patients, we assessed the correlation with the INCAT and MRC score. There was a weak correlation of GFV right hand 250 g of all CIDP patients with INCAT score  showed the same alterations of OI and PI compared to more disabled patients (INCAT-A ≥ 2).Beside sensory disturbance, the assessment of muscular weakness is essential in order to establish diagnosis as well as evaluate treatment outcome.So far, MRC and Martin’s Vigorimeter are established endpoints applied in clinical routine. Grip strength can be measured by using the Vigorimeter, a simple objective tool that is easy to apply , 16. HowThe medical research council scale (MRC) also works on the impairment level but has a great interrater variability and thus inherited imprecision. As a third outcome measure, the INCAT disability scale assesses disabling problems in daily arm and leg mobility and has evolved as the most established primary outcome in clinical trials since it was used in the large ICE trial of CIDP patients , 18. HowThe quantitative Q-Motor assessments were shown to detect subclinical changes in patients with premanifest Huntington’s disease and correlated well with disease severity , 14, 19 In the present study we show significantly elevated QIMA parameters in CIDP compared to HC. Subgroup analysis showed elevated OI and PI in atypical and typical CIDP compared with HC with no difference between both patient groups suggesting a good applicability also for atypical variants. Although the clinical picture differs markedly between CIDP subgroups, no differentiation has been performed in published studies , 18 whenIn particular, patients with atypical manifestation are misdiagnosed very frequently in almost 50% of all cases  based onWe acknowledge several limitations of this study. Although the sample size of 33 CIDP patients is comparatively large considering that CIDP is an orphan disease it is still too small to establish QIMA parameters as diagnostic and/or efficacy parameters in CIDP subgroups. This would need further confirmatory studies. MRC hasbeen obtained only from 22 patients. However, despite the limited number of MRC measurements, correlation with QIMA parameters reached statistically significance. In addition, grip strength parameters by Martin vigorimeter or Jamar , 26 haveRecently, Knak et al. showed that grip strength is less responsive to detect improvements after treatment than isokinetic dynamometry at ankles in a retrospective study. The authors concluded that grip strength as measured by JAMAR dynamometer does not seem to be an appropriate surrogate parameter of overall muscle strength and should be combined with isokinetic measurements of the lower limbs . In the Q-Motor tests may be useful to objectively assess muscular weakness in CIDP. The observations of our study encourage further exploration in larger cohort trials. In particular, QIMA parameters seem to be suitable to detect subclinical generalized muscle weakness in patients with milder disability and/or atypical phenotype. Therefore, they might be a sensitive and reliable endpoint in future CIDP trials and support data-driven, unbiased decision making in clinical development of novel therapies.


Nontraumatic pontine hemorrhage represents approximately 10% of all cases of nontraumatic intracranial hemorrhage. The predominant cause and symptom of pontine hemorrhage are hypertension and disturbance of consciousness, respectively.A 64-year-old man was transported to hospital by ambulance for sudden articulation disorder and right leg paralysis. He was neurologically alert with mild dysarthria, right leg paralysis, and increased deep tendon reflex in all limbs.Plain head computed tomography showed an approximately 1.5 mL hemorrhage in the dorsomedial pons.He was admitted to the Stroke Care Unit and received antihypertensive therapy.Around the time of admission, bilateral hearing loss suddenly developed with poorly defined wave V shown bilaterally on auditory brainstem response testing. As the hematoma subsequently resolved, the bilateral hearing loss recovered sufficiently to enable everyday conversation.We report herein a rare case of acute onset bilateral hearing loss caused by nontraumatic pontine hemorrhage. Pontine hemorrhage is often associated with disturbance of consciousness; however, care is required as latent communication disorder due to impaired hearing is possible regardless of the state of consciousness. As there are fundamentally no surgical options, treatment is usually conservative and outcomes are poor with a mortality rate of 40% to 60%. We report herein a rare case of dorsomedial pontine hemorrhage without change in consciousness in which the patient presented acute onset bilateral hearing loss immediately after hemorrhage onset that recovered as the hematoma subsequently resolved.Nontraumatic pontine hemorrhage represents approximately 10% of all cases of nontraumatic intracranial hemorrhage.2A 64-year-old man suddenly experienced articulation disorder and right leg paralysis immediately after exercise and was transported to our hospital by ambulance. He had a history of hypertension and was receiving oral combination antiplatelet therapy (100 mg aspirin and 75 mg clopidogrel) due to recent coronary stenting for angina.On arrival, his blood pressure was 223/103 mm Hg. Neurologically, he was alert  without ocular deviation or anisocoria. He presented mild dysarthria, right leg paralysis corresponding to Manual Muscle Test 4, and increased deep tendon reflex in all limbs . No pathological reflexes were elicited and no sensory or coordination abnormalities were observed. His National Institutes of Health Stroke Scale score was 1.Plain head computed tomography (CT) performed immediately after arrival showed an approximately 1.5 mL oval hemorrhage in the dorsomedial pons Fig. . On laboAntihypertensive therapy was immediately initiated and he was admitted to the Stroke Care Unit; however, around this time, he suddenly developed bilateral hearing loss and left tinnitus. He had difficulty hearing even when his ears were being directly shouted at. He was able to speak and communicate in writing and presented no aphasia. Otolaryngological examination found no abnormalities in the bilateral external auditory canal or tympanic membrane. On auditory brainstem response (ABR) testing on hospital day 16, poorly defined wave V was shown bilaterally indicating injury in the lower and central pons Table . Antihyp3; however, reports of this complication after pontine hemorrhage are rare.,4–7 Hearing loss can be generally divided into 2 types: sensorineural and conductive. Sensorineural hearing loss accounts for about 90% of reported hearing loss and can be caused by damage to any of the structures of the auditory pathway: the cochlea, vestibulocochlear nerve, cochlear nucleus, temporal lobe, inferior colliculus, and auditory cortex. The auditory pathway begins with hair cells distributed in the organ of Corti in the inner ear. They pass information to spiral ganglia, which house the nerve cell bodies in the cochlea. The axons of these nerves form the cochlear nerve and pass through the inner ear together with the vestibular nerve, entering the brainstem laterally to the pons. Soon after entering the cranium, fibers from this vestibulocochlear nerve bifurcate, synapsing in the dorsal and ventral cochlear nuclei. From the cochlear nuclei, the fibers ascend bilaterally in the lateral lemnisci and enter the medial geniculate body. On the way, some fibers synapse in the trapezoid body or lateral lemniscus and, after exiting the trapezoid body, ascend in the central auditory pathway to communicate bilaterally with the inferior colliculus, thereby providing the auditory cortex with auditory information from both cochlear nuclei. Therefore, bilateral hearing loss in cases of cerebral injury or pontine hemorrhage such as the present patient is extremely rare. However, in cases of major hemorrhage that extends across the bilateral cochlear nuclei, hearing loss accompanied by disturbance of consciousness due to damage to the reticular formation may occur. In such cases, disturbance of consciousness is likely to prevent patients reporting the hearing loss.Post-stroke hearing loss can occur due to injury in the distribution of the anterior inferior cerebellar artery while Chung et al reported that the hematoma and surrounding edema compressed the bilateral cochlear nuclei. Compared to previous reports, the present case was characterized by the small hematoma volume and the absence of concurrent disturbance of consciousness at hemorrhage onset. Furthermore, in the present patient, bilateral hearing loss began on the day of hospital admission, which is earlier than in previous reports (Table To our knowledge, only 2 cases of acute onset bilateral hearing loss following pontine hemorrhage have been reported. In both cases, the hematoma was large and hearing loss developed some time after pontine hemorrhage onset. With regard to etiology, Kim et al proposed that the pontine hematoma injured the bilateral cochlear nuclei and trapezoid body,The present study had several limitations. First, as the patient was transferred to another hospital immediately after spontaneous hearing recovery, ABR was not repeated. Second, at our hospital, we were unable to perform the otoacoustic emission test performed in previous reports.In the present patient, the location of hematoma in the dorsomedial pons and the abnormalities in waves V on ABR indicate trapezoid body and lateral lemniscus injury. Furthermore, as symptoms improved with hematoma resolution, the injury was more likely to be in the form of indirect transient damage due to the compression by hematoma and surrounding edema rather than direct destructive damage to the auditory pathway. The predominant symptom in pontine hemorrhage is most commonly disturbance of consciousness caused by damage to the reticular formation and it is likely that any impaired hearing is overlooked in patients in this state. Therefore, care is required as latent communication disorder due to impaired hearing is possible regardless of the state of consciousness.Conceptualization: Masashi Hoshino.Data curation: Hisanao Akiyama, Satoru Kashima, Kaima Soga, Takahiro Shimizu.Writing – original draft: Masashi Hoshino.Writing – review and editing: Hisanao Akiyama, Yasuhiro Hasegawa.Masashi Hoshino orcid: 0000-0002-6798-0571.