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The circadian system, which is essential for the alignment of sleep/wake cycles, modulates adult neurogenesis. The olfactory epithelium (OE) has the ability to generate new neurons throughout life. Loss of olfactory sensory neurons (OSNs) as a result of injury to the OE triggers the generation of new OSNs, which are incorporated into olfactory circuits to restore olfactory sensory perception. This regenerative potential means that it is likely that the OE is substantially affected by sleep deprivation (SD), although how this may occur remains unclear. The aim of this study is to address how SD affects the process of OSN regeneration following OE injury. Mice were subjected to SD for 2 weeks, which induced changes in circadian activity. This condition resulted in decreased activity during the night-time and increased activity during the daytime, and induced no histological changes in the OE. However, when subjected to SD during the regeneration process after OE injury, a significant decrease in the number of mature OSNs in the dorsomedial area of the OE, which is the only area containing neurons expressing NQO1 (quinone dehydrogenase 1), was observed compared to the NQO1-negative OE. Furthermore, a significant decrease in proliferating basal cells was observed in the NQO1-positive OE compared to the NQO1-negative OE, but no increase in apoptotic OSNs was observed. These results indicate that SD accompanied by disturbed circadian activity could induce structurally negative effects on OSN regeneration, preferentially in the dorsomedial area of the OE, and that this area-specific regeneration delay might involve the biological activity of NQO1.

We investigated whether the oxidoreductase cofactor pyrroloquinoline quinone (PQQ) prevents noise-induced and age-related hearing loss (NIHL and ARHL) in mice. To assess NIHL, 8 week-old mice with and without PQQ administration were exposed to noise for 4 h. PQQ was orally administered for one week before and after noise exposure and subcutaneously once before noise exposure. For ARHL evaluation, mice were given drinking water with or without PQQ starting at 2 months of age. In the NIHL model, PQQ-treated mice had auditory brainstem response (ABR) thresholds of significantly reduced elevation at 8 kHz, a significantly increased number of hair cells at the basal turn, and significantly better maintained synapses beneath the inner hair cells compared to controls. In the ARHL model, PQQ significantly attenuated the age-related increase in ABR thresholds at 8 and 32 kHz at 10 months of age compared to controls. In addition, the hair cells, spiral ganglion cells, ribbon synapses, stria vascularis and nerve fibers were all significantly better maintained in PQQ-treated animals compared to controls at 10 months of age. These physiological and histological results demonstrate that PQQ protects the auditory system from NIHL and ARHL in mice.

Objective To determine if the COVID-19 vaccine can cause vestibular neuritis (VN). Design Retrospective study. Setting Vertigo outpatient clinic of the Department of Otolaryngology JR Tokyo General Hospital. Participants: 378 patients who presented at the Vertigo clinic between July 2018 and March 2022 Results 23 out of 378 cases were diagnosed with vestibular neuritis. There was a significant seasonal bias of the onset of VN in 2021-3Q compared to other seasons. All 7 patients diagnosed with VN whose onset was 2021-3Q and 2021-4Q had received the BNT162b2 (Pfizer-BioNTech) vaccine within the previous 3 months and one patient diagnosed with VN whose onset was 2022-1Q had a history of COVID-19 infection six months earlier. Conclusions VN should be recognized as one of the side-effects of the BNT162b2 COVID-19 vaccination.

Mitochondrial dysfunction has been implicated in numerous common diseases as well as aging and plays an important role in the pathogenesis of sensorineural hearing loss (SNHL). In the current study, we showed that supplementation with germanium dioxide (GeO

Time restricted feeding (TRF), which is an intermittent fasting protocol, has been reported to decrease the toxicity and mortality rate associated with systemic gentamicin (GM) administration. The aim of this study is to evaluate the effect of TRF on GM-induced vestibular and auditory function in mice.Japan Central Laboratory for Experimental Animals:Institute of Cancer Research (Jcl:ICR) mice were housed in a light-dark (LD) cycle (12:12) and were divided into three groups: (1) GM treatment at a dose of 220 mg/kg with TRF (feeding time: 8 h [9:00-17:00] during the light phase [7:00-19:00]) (GM + TRF group), (2) GM treatment at a dose of 220 mg/kg without TRF (GM group), and (3) saline injection with TRF (NS + TRF group). GM or saline was injected subcutaneously for 18 days (three courses of 5 days' injection + 2 days' rest, and an additional 3 days' injection). The auditory brainstem response (ABR) and vestibular evoked potential (VsEP) were tested after the treatments. The number of sensory hair cells in the cochlear organs and the vestibular organs were quantified using microscopic images.All animals survived until the end of the experiment. One day after the last injection, GM + TRF mice showed significantly lower ABR thresholds at 4 kHz compared to GM mice, and there was no significant difference between the GM + TRF and NS + TRF groups. There was a significant difference of VsEP between GM and GM + TRF mice only in symmetric parabolic waves with linear acceleration and ramps waveform stimulation. GM + TRF mice showed significantly less outer and inner hair cell loss compared to GM mice. GM + TRF mice showed significantly less type II hair cell loss in the utricle and the ampulla compared to GM mice.TRF with daytime feeding reduced GM cytotoxicity in the cochlea and vestibular organs of ICR mice.NA.

The aim of this study was to investigate the effects of pyrroloquinoline quinone (PQQ), an oxidoreductase cofactor, on the H2O2-induced premature senescence model in HEI-OC1 auditory cells and to elucidate its mechanism of action in vitro. Cells were treated with PQQ for 1 day before H2O2 (100 μM) exposure. Mitochondrial respiratory capacity was damaged in this premature senescence model but was restored in cells pretreated with PQQ (0.1 nM or 1.0 nM). A decrease in mitochondrial potential, the promotion of mitochondrial fusion and the accelerated movement of mitochondria were all observed in PQQ-pretreated cells. The protein expression of sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) were significantly decreased under H2O2 exposure while they were increased with PQQ pretreatment, and PGC-1α acetylation was significantly decreased. In conclusion, PQQ has a protective effect on the premature senescence model of HEI-OC1 auditory cells and is associated with the SIRT1/PGC-1α signaling pathway, mitochondrial structure, and mitochondrial respiratory capacity.

It remains unclear whether the dominance of 1000 Hz responses over responses at 500 Hz in cervical vestibular evoked myogenic potentials (cVEMPs) are characteristic of endolymphatic hydrops (EH), due to the presence of patients with absent responses at both frequencies. The purpose of the present study is to examine whether the dominant cVEMP responses at 1000 Hz over 500 Hz are characteristic findings of EH-related diseases among patients who show various cVEMP findings.We retrospectively reviewed the medical records of 470 consecutive patients who underwent cVEMP testing with short-tone bursts at both 500 Hz and 1000 Hz. We categorized the cVEMP responses of these 470 patients into the following five groups: (group 1) present responses at both frequencies bilaterally, (group 2) present responses at 500 Hz but absent at 1000 Hz on at least one side, (group 3) absent responses at 500 Hz but present at 1000 Hz on at least one side, (group 4) absent responses at both frequencies on one side and present at both frequencies on the other side, and (group 5) absent responses at both frequencies bilaterally. We compared the proportion of EH-related diseases between each group and the other four groups and then investigated any increased or decreased disease incidence in each group.In group 3, the proportion of EH-related disease was significantly higher (p0.01), and the incidence of an EH-related disease was greatly increased (standard residual value3).cVEMPs that are absent at 500 Hz and present at 1000 Hz may be characteristic of EH-related disease.

Background:Vestibular dysfunction is a complication of cochlear implantation (CI). Reports on the evaluation of vestibular function before and after CI are limited, especially in children. We investigated the effect of CI on vestibular function in pediatric patients.Patients and Methods:We routinely evaluated vestibular function before but not immediately after CI. Therefore, patients who underwent sequential bilateral CI were enrolled in this study. Seventy-three children who underwent sequential CI from 2003 to 2020 at our hospital were included. Since the vestibular function of the first implanted ear was evaluated before the second surgery for the contralateral ear, post-CI evaluation timing differed among the cases. The evaluation included a caloric test, a cervical vestibular-evoked myogenic potential (cVEMP) test, and a damped rotation test. The objective variables included the results of these tests, and the explanatory variables included the age at surgery, cause of hearing loss, electrode type, and surgical approach used. The associations of these tests were analyzed.Results:cVEMP was the most affected after CI (36.1%), followed by the caloric test (23.6%), and damped rotation test (7.8%). Cochleostomy was significantly more harmful than a round window (RW) approach or an extended RW approach based on the results of the caloric test (p= 0.035) and damped rotation test (p= 0.029). Perimodiolar electrodes affected the caloric test results greater than straight electrodes (p= 0.041). There were no significant associations among these tests' results.Conclusions:Minimally invasive surgery in children using a round window approach or an extended round window approach with straight electrodes is desirable to preserve vestibular function after CI.

Abnormal vestibular function has been reported in patients with vestibular migraine (VM). However, it is unclear whether the proportion of patients with vestibular dysfunction differs between the diagnoses of VM and probable VM (PVM).We reviewed the medical records of 1736 patients who underwent cervical vestibular-evoked myogenic potential testing to air-conducted sound (ACS cVEMP), ocular VEMP testing to bone-conducted vibration (BCV oVEMP), and caloric testing. We used the diagnostic criteria for VM provided in the appendix of the International Classification of Headache Disorders 3 Beta, and the diagnostic criteria consensus published by the Barany Society and the International Headache Society for PVM. Twenty-two VM patients and a further 22 PVM patients were included. Binomial logistic regression analyses were performed to see whether the subjects' age, sex, or the diagnostic certainty of VM (i.e., VM vs. PVM) have an association with the presence of vestibular dysfunction.There was no significant association between the diagnostic certainty of VM and abnormality in caloric or ACS cVEMP testing. On the other hand, VM had a significant positive association with abnormality in BCV oVEMPs compared with PVM.VM is associated with dysfunction of the utriculo-ocular pathway more frequently than PVM, suggesting that the pathophysiology of VM involves the utriculo-ocular pathway.

Objective: To evaluate various machine learning algorithms in predicting peripheral vestibular dysfunction using the dataset of the center of pressure (COP) sway during foam posturography measured from patients with dizziness. Study Design: Retrospective study. Setting: Tertiary referral center. Patients: Seventy-five patients with vestibular dysfunction and 163 healthy controls were retrospectively recruited. The dataset included the velocity, the envelopment area, the power spectrum of the COP for three frequency ranges and the presence of peripheral vestibular dysfunction evaluated by caloric testing in 75 patients with vestibular dysfunction and 163 healthy controls. Main Outcome Measures: Various forms of machine learning algorithms including the Gradient Boosting Decision Tree, Bagging Classifier, and Logistic Regression were trained. Validation and comparison were performed using the area under the curve (AUC) of the receiver operating characteristic curve (ROC) and the recall of each algorithm using K-fold cross-validation. Results: The AUC (0.90 ± 0.06) and the recall (0.84 ± 0.07) of the Gradient Boosting Decision Tree were the highest among the algorithms tested, and both of them were significantly higher than those of the logistic regression (AUC: 0.85 ± 0.08, recall: 0.78 ± 0.07). The recall of the Bagging Classifier (0.82 ± 0.07) was also significantly higher than that of logistic regression. Conclusion: Machine learning algorithms can be successfully used to predict vestibular dysfunction as identified using caloric testing with the dataset of the COP sway during posturography. The multiple algorithms should be evaluated in each clinical dataset since specific algorithm does not always fit to any dataset. Optimization of the hyperparameters in each algorithm are necessary to obtain the highest accuracy.

Ameliorating effect of noisy galvanic vestibular stimulation (nGVS) on posture varies among subjects. In this feasibility study, we investigated the association between original postural instability and the ameliorating effect of nGVS on posture. Data were collected in a previously published study. Thirty healthy elderly were recruited. Two nGVS sessions (30 min or 3 h) were performed in a randomised order. The optimal intensity of nGVS, the most effective intensity for improving posture, was determined before each session. Posture was measured for 30 s during and after nGVS in the eyes-closed/foam rubber condition. The velocity, envelopment area, and root mean square of the centre of pressure movement without nGVS were significantly larger in the group with an optimal intensity than those in the group without an optimal intensity. There was a significant positive correlation between these values and the long-term ameliorating effects. The ratio of the values in the eyes-closed/foam rubber condition to those in the eyes-open condition was significantly larger in the group with an optimal intensity, and had a significant correlation with the long-term ameliorating effects. The ameliorating effects are greater in subjects who were originally unstable and in those whose postural stability was relatively independent of vestibular input.

OBJECTIVE To determine parameters in computed tomography (CT) of the temporal bone that would be useful for prediction of cerebrospinal fluid (CSF) gusher during cochlear implantation (CI) surgery and postoperative facial nerve stimulation (FNS) in patients with inner ear malformations. STUDY DESIGN Retrospective study. SETTING Tertiary referral center. PATIENTS Three hundred seventy-five cases who had undergone CI surgery including 54 inner ear malformation cases were analyzed. MAIN OUTCOME MEASURES The diameters of the cochlea modiolar base and porus of the internal auditory canal (IAC), length of IAC, diameter of the vestibular aqueduct (VA) at the operculum, and presence or absence of the modiolus of the cochlea were evaluated by using CT. RESULTS CSF gusher occurred in 12 (22%) cases, in whom the diameters of the cochlea modiolar base (2.7 ± 0.6 mm, p

Objective:To investigate the influence of vestibular function on dynamic postural stability assessed by the functional reach test (FRT) and the timed up and go test (TUG).Study design:Retrospective study.Setting:Tertiary referral center.Subjects and Methods:The FRT and TUG were performed in 399 patients with dizziness. The effects of peripheral vestibular dysfunction assessed by the caloric test and cervical vestibular evoked myogenic potentials (cVEMPs) to air-conducted sound (500 Hz, tone burst) on the results of FRT and TUG were analyzed.Results:Neither FRT nor TUG scores showed significant differences in relation to the results of the caloric test ( P > .3). The FRT scores in patients who showed abnormal cVEMP responses on both sides were significantly smaller than those in patients who showed normal cVEMP responses ( P < .01). The TUG scores in patients who showed abnormal cVEMP responses on both sides were significantly greater than those in patients who showed normal cVEMP responses ( P < .05).Conclusion:The vestibulo-spinal reflex mediated by the saccule and its afferents is one of the factors that influence the maintenance of dynamic postural stability as measured by FRT and TUG.

Objective To determine minimally important differences (MIDs) for subjective improvement in postural stability after a therapeutic intervention in patients with bilateral vestibulopathy (BVP). Methods Thirteen BVP patients received noisy galvanic vestibular stimulation (nGVS) for 30 min and their static posture with eyes closed was monitored after the stimuli. The velocity of the center of pressure (COP) movement, the area enclosed by the COP movement, and the root mean square (RMS) of the displacement of the COP were measured for 30 s. Subjective evaluation of postural stability after nGVS was graded as worsened, slightly worsened, unchanged, slightly improved and improved in comparison with postural stability measured without nGVS. Anchor-based methods were used to estimate MIDs for subjective improvement. Velocity, area and RMS for each anchor-response group were averaged (2 sessions, each with 5 measurement periods during 3 h after the stimuli). The mean changes between the slightly improved group and unchanged group were used as estimates for MID for improvement. Results A total of 129 anchors were analyzed. Subjective evaluations numbered 83 (64%) for unchanged and 33 (26%) for slightly improved. Anchor-based methods yielded estimates for MIDs of -0.43 cm/s in velocity improvement (p Conclusion The present study provides the estimation of MIDs for improving postural stability in BVP patients and may be useful for interpreting whether the results from clinical trials are meaningful in future studies.

CI improves hearing thresholds and auditory skills in children with most types of inner ear malformations. However, the development of sound detection skills is not as good as it is in children without inner ear malformations.To investigate the influence of inner ear malformations on development of auditory skills after cochlear implantation (CI).Records of 20 children with inner ear malformations who underwent cochlear implantation before 4 years of age and followed up for more than 2 years were retrospectively reviewed. Hearing thresholds, the Meaningful Auditory Integration Scale (MAIS), and Meaningful Use of Speech Scale (MUSS) scores before and after CI were analyzed and compared with 20 age-matched deaf children who underwent CI.The children with inner ear malformations showed significant improvements in hearing thresholds and the MAIS and MUSS scores 1 year after CI (p 0.01). However, their development of the MAIS scores was significantly delayed compared to children without inner ear malformations (p 0.05), while there was no significant difference in development of the MUSS scores between them. Significant improvements in hearing thresholds and the MAIS and MUSS scores were observed in cochlear hypoplasia and incomplete partition (p 0.05).

Vertigo attacks in IBV patients involving both the superior and inferior vestibular nerve systems were significantly more severe than vertigo attacks in patients with selective involvement of the inferior vestibular nerve system alone.To investigate the relationship between the frequency and duration of vertigo and the affected vestibular nerve system in idiopathic bilateral vestibulopathy (IBV).This study categorized 44 IBV patients into the following three sub-groups according to the affected vestibular nerve system: superior, inferior, and mixed type. These patients were also categorized into the following three sub-groups according to their clinical time course: progressive type showing no episodes of vertigo, sequential type showing recurrent vertigo attacks and single-attack type showing a single episode of vertigo.Ten, 11 and 23 patients were classified as the superior, the inferior, and the mixed type, respectively. Seventeen, 23, and four patients were classified as the progressive, the sequential, and the single-attack type, respectively. For the patients having one or more vertigo attacks, the duration of the vertigo attack was longer than 24 h in 69% of the mixed type, and the duration of vertigo in the mixed type was significantly longer than that in the inferior type (p 0.05).

We aimed at determining the mitochondrial function in premature senescence model of auditory cells. Short exposure to H2O2 (1 h, 0.1 mM) induced premature cellular senescence in House Ear Institute-Organ of Corti 1 auditory cells. The transmission electron microscopy analysis revealed that damaged mitochondria and autophagosomes containing dense organelles appeared in the auditory cells after short exposure to H2O2. The branch and junction parameters of the skeletonized image of the mitochondria were found to decrease significantly in H2O2-treated cells. A branched reticulum of tubules was poorly formed, featuring coexistence of numerous tiny clusters along with few relatively large entities in the H2O2-treated cells. In terms of bioenergetics, H2O2-treatment led to the dose-dependent decrease in mitochondrial membrane potential in the auditory cells. The fragmented mitochondria (fusion fission) was slightly lower than the control cells. The short-time exposure of live auditory cells to H2O2 damaged the mitochondrial respiratory capacity without any effect on the baseline ATP production rates. The vulnerability of the mitochondrial membrane potential to the uncoupling reagent was increased after H2O2 treatment. Our findings indicated that the mitochondrial dysfunction due to the decline in the O2 consumption rate should be the first event of premature senescence process in the auditory cells, resulting in the imbalance of mitochondrial fusion/fission and the collapse of the mitochondrial network., Auditory system senescence: Mitochondrial dynamics and respiration The mitochondrial morphology and physiology could influence the process of age-related hearing loss. Prof. Tatsuya Yamasoba’s research group at the University of Tokyo has examined the functional changes of mitochondria in terms of its respiratory function, membrane potential and morphology under premature senescence induced by oxidative stress in an auditory cell line. The morphological and functional mitochondrial damage were observed as the respiratory capacity deficiency and the fluctuation of the fusion/fission balance. Their results provide evidence of the fundamental interdependence between mitochondrial metabolic activity and its network structure in premature senescence process of auditory cells. This is a pioneer study to indicate the influence of mitochondrial dynamics and respiratory system on the premature senescence process of auditory cells. Further studies into inter cellular communication including cytoskeleton and nucleus can help us understand the etiology underlying age-related hearing loss.

Reactive oxygen species (ROS) generation is one of the mechanisms underlying noise-induced hearing loss (NIHL). Manganese superoxide dismutase (Mn-SOD), an antioxidant enzyme acting within the mitochondria, converts toxic superoxide to hydrogen peroxide. We investigated the role of Mn-SOD in NIHL by examining the extent of hearing loss and hair cell damage after noise exposure in C57BL/6 wild-type (WT) mice and Mn-SOD heterozygous knockout (HET) mice (n = 6 each). Both HET and WT mice were exposed to 120 dB sound pressure level at 4 kHz octave band noise for 4 h. Auditory brainstem responses (ABRs) were used to evaluate hearing thresholds before noise exposure, and at 1 h, and 1, 3, 7, and 14 days after exposure. The mice were euthanized 14 days after noise exposure for examination of the cochlear pathology. Mean ABR thresholds were similarly elevated at all frequencies in both groups 1 h after noise exposure, but were significantly worse, particularly at 4 kHz, on post-noise exposure days 7 and 14 in HET mice compared with WT mice. Outer hair cell damage was significantly greater in all cochlear turns in HET mice compared with WT mice. Collectively, these findings suggest that Mn-SOD plays an important role in protecting the cochlea from noise-induced damage.

Objective:To investigate the clinical features and vestibular symptoms of patients with abnormal ocular vestibular evoked myogenic potentials (oVEMPs) and/or cervical VEMPs (cVEMPs) in the presence of normal caloric responses.Study Design:Retrospective chart review.Setting:Tertiary referral center.Methods:One thousand five hundred twenty-one consecutive patients with balance problems who underwent the caloric, cVEMP, and oVEMP tests were included, and patients who showed abnormal oVEMPs and/or cVEMPs in the presence of normal caloric responses were selected. Clinical characteristics, diagnoses, and vestibular symptoms of the patients were analyzed.Results:Of the 1521 patients, 227 (15%) were found to have abnormal oVEMPs and/or cVEMP responses with normal caloric responses. Benign paroxysmal positional vertigo (BBPV), Meniere’s disease, and vestibular migraine were the common diagnoses of these patients. Eighty-one patients (36%) could not be diagnosed with a recognizable disease. Multiple episodes of spinning vertigo with a duration of seconds to hours were their most common vestibular symptoms.Conclusion:BPPV, Meniere’s disease, and vestibular migraine are the most frequent diagnoses showing abnormal oVEMP and/or cVEMPs without canal paresis. Apart from these clinical entities, a portion of undiagnosed patients with multiple episodes of vertigo might have a disease that involves the otolith organs only.

OBJECTIVE To assess the frequency-domain characteristics of postural instability caused by peripheral vestibular dysfunction by performing a power spectral analysis of the center of pressure (COP) sway during foam posturography. METHODS Data were obtained from 78 patients and 163 controls. Two-legged stance tasks were performed in 4 conditions: eyes open with and without foam rubber, and eyes closed with and without foam rubber. We estimated the power spectrum of the acceleration signal using the maximum entropy method. The areas under the curve (AUCs) of power spectral density of the COP were calculated across low-frequency (0.02 to 0.1 Hz, LF-AUC), middle-frequency (0.1 to 1Hz, MF-AUC), and high-frequency (1 to 10 Hz, HF-AUC) ranges. We performed binomial logistic regression analyses to see whether the AUCs of selected bandwidths of COP have a stronger association with the presence of peripheral vestibular dysfunction in comparison with the velocity and area in the eyes closed/foam rubber condition. RESULTS In both the controls and patients, the MF-AUC was significantly larger than the LF-AUC or HF-AUC in the eyes closed/foam rubber condition. In this condition, the presence of peripheral vestibular dysfunction had a significantly positive relationship with MF-AUC and HF-AUC (p < 0.05) and the MF-AUC of the anterior-posterior axis showed a stronger association with the presence of peripheral vestibular dysfunction than area. CONCLUSION An increase in activity at middle frequency movements could be characteristic of peripheral vestibular dysfunction when standing on foam rubber with the eyes closed.