TMC function, dysfunction, and restoration in mouse vestibular organs.

Tmc1 and Tmc2 are essential pore-forming subunits of mechanosensory transduction channels localized to the tips of stereovilli in auditory and vestibular hair cells of the inner ear. To investigate expression and function of Tmc1 and Tmc2 in vestibular organs, we used quantitative polymerase chain reaction (qPCR), fluorescence in situ hybridization - hairpin chain reaction (FISH-HCR), immunostaining, FM1-43 uptake and we measured vestibular evoked potentials (VsEPs) and vestibular ocular reflexes (VORs). We found that Tmc1 and Tmc2 showed dynamic developmental changes, differences in regional expression patterns, and overall expression levels which differed between the utricle and saccule. These underlying changes contributed to unanticipated phenotypic loss of VsEPs and VORs in Tmc1 KO mice. In contrast, Tmc2 KO mice retained VsEPs despite the loss of the calcium buffering protein calretinin, a characteristic biomarker of mature striolar calyx-only afferents. Lastly, we found that neonatal Tmc1 gene replacement therapy is sufficient to restore VsEP in Tmc1 KO mice for up to six months post-injection.

Nestin-expressing cells are mitotically active in the mammalian inner ear.

Nestin expression is associated with pluripotency. Growing evidence suggests nestin is involved in hair cell development. The objective of this study was to investigate the morphology and role of nestin-expressing cells residing in the early postnatal murine inner ear. A lineage-tracing nestin reporter mouse line was used to further characterize these cells. Their cochleae and vestibular organs were immunostained and whole-mounted for cell counting. We found Nestin-expressing cells present in low numbers throughout the inner ear. Three morphotypes were observed: bipolar, unipolar, and globular. Mitotic activity was noted in nestin-expressing cells in the cochlea, utricle, saccule, and crista. Nestin-expressing cell characteristics were then observed after hair cell ablation in two mouse models. First, a reporter model demonstrated nestin expression in a significantly higher proportion of hair cells after hair cell ablation than in control cochleae. However, in a lineage tracing nestin reporter mouse, none of the new hair cells which repopulated the organ of Corti after hair cell ablation expressed nestin, nor did the nestin-expressing cells change in morphotype. In conclusion, Nestin-expressing cells were identified in the cochlea and vestibular organs. After hair cell ablation, nestin-expressing cells did not react to the insult. However, a small number of nestin-expressing cells in all inner ear tissues exhibited mitotic activity, supporting progenitor cell potential, though perhaps not involved in hair cell regeneration.

A reliable and reproducible protocol for sound-evoked vestibular myogenic potentials in rattus norvegicus.

Introduction: Cervical vestibular evoked myogenic potentials (cVEMPs) provide an objective measure of the integrity of the sacculo-collic pathway leading to their widespread use as a clinical tool in the diagnostic vestibular test battery. Though the application of cVEMPs in preclinical models to assess vestibular function, as performed in relevant clinical populations, remains limited. The present study aimed to establish a rodent model of cVEMP with standardized methods and protocols, examine the neural basis of the responses, and characterize and validate important features for interpretation and assessment of vestibular function. Methods: We compared air-conducted sound (ACS)-evoked VEMPs from the sternocleidomastoid muscles in naïve Brown Norway rats. A custom setup facilitated repeatable and reliable measurements which were carried out at multiple intensities with ACS between 1 and 16 kHz and over 7 days. The myogenic potentials were identified by the presence of a positive (P1)-negative (N1) waveform at 3-5 ms from the stimulus onset. Threshold, amplitude, and latency were compared with intensity- and frequency-matched responses within and between animals. Results: cVEMP responses were repeatedly evoked with stimulus intensities between 50-100 dB SPL with excellent test-retest reliability and across multiple measurements over 7 days for all frequencies tested. Suprathreshold, cVEMP responses at 90 dB SPL for 6-10 kHz stimuli demonstrated significantly larger amplitudes (p < 0.01) and shorter latencies (p < 0.001) compared to cVEMP responses for 1-4 kHz stimuli. Latency of cVEMP showed sex-dependent variability, but no significant differences in threshold or amplitude between males and females was observed. Discussion: The results provide a replicable and reliable setup, test protocol, and comprehensive characterization of cVEMP responses in a preclinical model which can be used in future studies to elucidate pathophysiological characteristics of vestibular dysfunctions or test efficacy of therapeutics.

Transient connection between the vestibular aqueduct and utricle: A study using sagittal sections of human embryonic heads.

BACKGROUND: The aqeductus vestibuli (aqueduct) is believed to connect to the saccule in embryos and adults. However, in embryos, the saccule and utricle are known to communicate widely to provide a common endolymph space "atrium". METHODS: Using sagittal histological sections from five embryos (crown-rump length or CRL, 14-21 mm), nine early fetuses (CRL 24-35 mm) and 12 midterm and near-term fetuses (CRL 82-272 mm), we revisited the development and growth of the human ear aqueduct. RESULTS: The atrium took on a thick tube-like appearance as an antero-inferior continuation of the aqueduct, but soon divided into multiple gulfs. Most of the gulfs corresponded to the ampullae of semicircular ducts, while one gulf at the antero-medio-inferior corner corresponded to the future saccule. Notably, in eight of the 14 embryos and early fetuses, the aqueduct ended at the utricle near the primitive ampulla of the anterior (superior) or posterior semicircular duct. Conversely, an embryo of CRL 21 mm was the smallest specimen in which the aqueduct joined the gulf-like saccule. At midterm and near-term, the growing perilymph space separated the aqueduct from the utricle and appeared to push the aqueduct toward the saccule. A topographical change occurred between the embryonic superiorly located utricle and the inferiorly-located saccule to create the antero-posterior arrangement in adults. CONCLUSIONS: Consequently, the vestibular end of the aqueduct was most likely to migrate anteriorly from the utricle to the saccule at 6-8 weeks possibly due to differential growth of the endothelium. Previous reconstructions of the embryonic aqueduct might be biased by the adult morphology.

Subjective Visual Vertical and Vestibular Evoked Myogenic Potential in Meniere's disease,

Abstract Objective To evaluate otolith function by comparing the findings of the Subjective Visual Vertical, the cervical Vestibular Evoked Myogenic Potential and the ocular Vestibular Evoked Myogenic Potential tests in patients in the inter-crisis period of unilateral definite Meniere's disease. Methods The sample consisted of an experimental group (n = 22; 10 men and 12 women, mean age 47.32 ± 12.82 years) with definite unilateral Meniere's disease and a control group (n = 14; 5 men and 9 women, with a mean age of 41.64 ± 13.45 years). They all underwent vestibular evaluation by means of Subjective Visual Vertical with the bucket method and, cervical and ocular Vestibular Evoked Myogenic Potential tests. The data were collected and subjected to statistical analysis. Results The results of the comparison of the Subjective Visual Vertical, the cervical Vestibular Evoked Myogenic Potential, the ocular Vestibular Evoked Myogenic Potential and, the association of cervical Vestibular Evoked Myogenic Potential with the ocular Vestibular Evoked Myogenic Potential showed no significant difference, indicating concordance among the tests. Conclusion The identified abnormalities and the concordance between the combined proportion of the Subjective Visual Vertical, the cervical Vestibular Evoked Myogenic Potential and the ocular Vestibular Evoked Myogenic Potential findings indicate that the association of these three tests contributes to the identification of sustained and transient otolith dysfunction in the inter-crisis of unilateral definite Meniere's disease. Level of evidence 2.

Histopathological reaction in the vestibule after cochlear implantation in Macaca fascicularis.

Cochlear implantation surgery (CI) is considered a safe procedure and is the standard treatment for the auditory rehabilitation in patients with severe-to-profound sensorineural hearing loss. Although the development of minimally traumatic surgical concepts (MTSC) have enabled the preservation of residual hearing after the implantation, there is scarce literature regarding the vestibular affection following MTCS. The aim of the study is to analyze histopathologic changes in the vestibule after CI in an animal model (Macaca fascicularis). Cochlear implantation was performed successfully in 14 ears following MTCS. They were classified in two groups upon type of electrode array used. Group A (n = 6) with a FLEX 28 electrode array and Group B (n = 8) with HL14 array. A 6-month follow-up was carried out with periodic objective auditory testing. After their sacrifice, histological processing and subsequent analysis was carried out. Intracochlear findings, vestibular presence of fibrosis, obliteration or collapse is analyzed. Saccule and utricle dimensions and neuroepithelium width is measured. Cochlear implantation was performed successfully in all 14 ears through a round window approach. Mean angle of insertion was >270° for group A and 180-270° for group B. In group A auditory deterioration was observed in Mf 1A, Mf2A and Mf5A with histopathological signs of scala tympani ossification, saccule collapse (Mf1A and Mf2A) and cochlear aqueduct obliteration (Mf5A). Besides, signs of endolymphatic sinus dilatation was seen for Mf2B and Mf5A. Regarding group B, no auditory deterioration was observed. Histopathological signs of endolymphatic sinus dilatation were seen in Mf 2B and Mf 8B. In conclusion, the risk of histological damage of the vestibular organs following minimally traumatic surgical concepts and the soft surgery principles is very low. CI surgery is a safe procedure and it can be done preserving the vestibular structures.

Binocular 3-D otolith-ocular reflexes: responses of chinchillas to natural and prosthetic stimulation after ototoxic injury and vestibular implantation.

The otolith end organs inform the brain about gravitational and linear accelerations, driving the otolith-ocular reflex (OOR) to stabilize the eyes during translational motion (e.g., moving forward without rotating) and head tilt with respect to gravity. We previously characterized OOR responses of normal chinchillas to whole body tilt and translation and to prosthetic electrical stimulation targeting the utricle and saccule via electrodes implanted in otherwise normal ears. Here we extend that work to examine OOR responses to tilt and translation stimuli after unilateral intratympanic gentamicin injection and to natural/mechanical and prosthetic/electrical stimulation delivered separately or in combination to animals with bilateral vestibular hypofunction after right ear intratympanic gentamicin injection followed by surgical disruption of the left labyrinth at the time of electrode implantation. Unilateral intratympanic gentamicin injection decreased natural OOR response magnitude to about half of normal, without markedly changing OOR response direction or symmetry. Subsequent surgical disruption of the contralateral labyrinth at the time of electrode implantation surgery further decreased OOR magnitude during natural stimulation, consistent with bimodal-bilateral otolith end organ hypofunction (ototoxic on the right ear, surgical on the left ear). Delivery of pulse frequency- or pulse amplitude-modulated prosthetic/electrical stimulation targeting the left utricle and saccule in phase with whole body tilt and translation motion stimuli yielded responses closer to normal than the deficient OOR responses of those same animals in response to head tilt and translation alone.NEW & NOTEWORTHY Previous studies to expand the scope of prosthetic stimulation of the otolith end organs showed that selective stimulation of the utricle and saccule is possible. This article further defines those possibilities by characterizing a diseased animal model and subsequently studying its responses to electrical stimulation alone and in combination with mechanical motion. We show that we can partially restore responses to tilt and translation in animals with unilateral gentamicin ototoxic injury and contralateral surgical disruption.

Application of supervised machine learning algorithms for the evaluation of utricular function on patients with Meniere's disease: utilizing subjective visual vertical and ocular-vestibular-evoked myogenic potentials.

BACKGROUND: Research on the otolith organs remains inconclusive. OBJECTIVES: This study seeks to further elucidate utricular function in patients with Meniere's disease (MD) in three ways: (1) We aimed to disambiguate the role of the Subjective Visual Vertical (SVV) and Ocular Vestibular Evoked Myogenic Potential (o-VEMP) tests regarding which utricular subsystem each is measuring. (2) We sought to characterize the acute and chronic state of MD by identifying differences in the relationship of SVV and o-VEMP results across patients with acute and chronic MD. (3) We attempted to find a machine-learning algorithm that could predict acute versus chronic MD using SVV and o-VEMP. METHODS: A prospective study with ninety subjects. RESULTS: (1) SVV and o-VEMP tests were found to have a moderate linear relationship in patients with acute MD, suggesting each test measures a different utricular subsystem. (2) Regression analyses statistically differed across the two patient populations, suggesting that SVV results were normalized in chronic MD patients. (3) Logistic regression and Naïve Bayes algorithms were found to predict acute and chronic MD accurately. SIGNIFICANCE: A better understanding of what diagnostic tests measure will lead to a better classification system for MD and more targeted treatment options in the future.

Subjective Visual Vertical and Vestibular Evoked Myogenic Potential in Meniere's disease.

OBJECTIVE: To evaluate otolith function by comparing the findings of the Subjective Visual Vertical, the cervical Vestibular Evoked Myogenic Potential and the ocular Vestibular Evoked Myogenic Potential tests in patients in the inter-crisis period of unilateral definite Meniere's disease. METHODS: The sample consisted of an experimental group (n=22; 10 men and 12 women, mean age 47.32±12.82 years) with definite unilateral Meniere's disease and a control group (n=14; 5 men and 9 women, with a mean age of 41.64±13.45 years). They all underwent vestibular evaluation by means of Subjective Visual Vertical with the bucket method and, cervical and ocular Vestibular Evoked Myogenic Potential tests. The data were collected and subjected to statistical analysis. RESULTS: The results of the comparison of the Subjective Visual Vertical, the cervical Vestibular Evoked Myogenic Potential, the ocular Vestibular Evoked Myogenic Potential and, the association of cervical Vestibular Evoked Myogenic Potential with the ocular Vestibular Evoked Myogenic Potential showed no significant difference, indicating concordance among the tests. CONCLUSION: The identified abnormalities and the concordance between the combined proportion of the Subjective Visual Vertical, the cervical Vestibular Evoked Myogenic Potential and the ocular Vestibular Evoked Myogenic Potential findings indicate that the association of these three tests contributes to the identification of sustained and transient otolith dysfunction in the inter-crisis of unilateral definite Meniere's disease.

Assessment of survey radiography as a method of diagnosing bilateral laryngeal paralysis in dogs.

The gold standard for diagnosis of laryngeal paralysis is laryngoscopy under light anesthesia. This prospective analytical cross-sectional study aimed to determine whether a radiographic assessment of the larynx could be used as a non-invasive screening tool for diagnosing laryngeal paralysis in non-sedated animals, as the laryngeal ventricles may appear wider in affected animals. The laryngeal ventricles of 18 dogs with bilateral laryngeal paralysis composing the affected group and 25 non-sedated dogs presenting no respiratory abnormality composing the control group were evaluated using right lateral radiography of the larynx. Three observers measured the ratios of the maximal ventricular length and surface to the body length of the third cervical vertebra (MVL/LC3 and VS/LC3, respectively). They also subjectively assessed the ventricular shape as either normal or rounded. The most accurate criterion was found to be MVL/LC3, as the respective areas under the ROC curves were 0.96 (95% confidence interval [CI]: 0.95-0.97), 0.89 (95% CI: 0.87-0.91), 0.80 (95% CI: 0.65-0.95) for MVL/LC3, VS/LC3, and ventricular shape evaluation, respectively. Based on ROC curve analysis, two thresholds of clinical interest were set for the MVL/LC3; bilateral laryngeal paralysis was very unlikely for values < 0.3 and very likely for values > 0.5. The findings of this study support the use of lateral laryngeal radiography as a screening tool for diagnosing bilateral laryngeal paralysis. However, further diagnostic tests remain required if MVL/LC3 lies between these threshold values or if clinically indicated. Further studies are warranted to explore the use of laryngeal radiography in unilateral paralysis and other laryngeal or oropharyngeal diseases.

Clinical effect of balloon pressurized kyphoplasty for fresh single-segment vertebral compression fractures / 国际外科学杂志

Objective:To study the clinical effect of balloon compression closure kyphoplasty in the treatment of fresh single-segment vertebral compression fracture.Methods:A retrospective study was used to analyze the clinical data of 80 patients with osteoporotic vertebral compression fracture (OVCF) admitted to Gansu Provincial Hospital of Traditional Chinese Medicine from June 2019 to June 2021. They were divided into two groups according to the surgical methods: the simple percutaneous kyphoplasty (PKP) group and the percutaneous kyphoplasty compression group, with 40 patients in each group. The PKP group was routinely treated with PKP, and the PKP compression group was treated with balloon compression occlusion technology on the basis of the PKP group. The amount of bone cement injected, the leakage of bone cement, the height of the anterior edge of the injured vertebra, the Cobb angle of kyphosis, the visual analogue score (VAS) and the Oswestry dysfunction index (ODI) were compared between the two groups. The measurement data conforming to the normal distribution were expressed as ( ± s), and the comparison between the two groups was conducted by t-test; The counting data were expressed by n(%) and the comparison between the two groups adopts Chi-square or Fisher exact probability. Results:The amount of bone cement injected and the leakage rate of bone cement in the PKP compression group were significantly higher than those in the simple PKP group ( P<0.05). The height of the anterior edge of the injured vertebra in the two groups was significantly higher than that before the operation on the first day and three months after the operation ( P<0.05). The Cobb angle, VAS score and ODI index of the injured vertebra in the two groups were significantly lower than that before the operation on the first day and three months after the operation ( P<0.05). The height of the anterior edge of the injured vertebra in the PKP compression group was significantly higher than that in the PKP group ( P<0.05). The Cobb angle of kyphosis in the PKP compression group was significantly lower than that in the simple PKP group at 1 day and 3 months after operation ( P<0.05). There was no significant difference in VAS score between PKP compression group and PKP group on 1 day after operation ( P>0.05), and compared with PKP group on 3 months after operation ( P<0.05). There was no significant difference in the ODI index between the PKP compression group and the two groups 1 day and 3 months after PKP ( P>0.05). Conclusion:Balloon compression closure technology can significantly reduce the leakage of bone cement in PKP and increase the amount of bone cement injected, which is beneficial to reduce the pain of vertebral body and improve the function of OVCF patients, and can improve the clinical treatment effect, which is worth promoting.

When, where, and why should we look for vestibular dysfunction in people with diabetes mellitus?

The biochemistry of diabetes mellitus results in multi-system tissue compromise that reduces functional mobility and interferes with disease management. Sensory system compromise, such as peripheral neuropathy and retinopathy, are specific examples of tissue compromise detrimental to functional mobility. There is lack of clarity regarding if, when, and where parallel changes in the peripheral vestibular system, an additional essential sensory system for functional mobility, occur as a result of diabetes. Given the systemic nature of diabetes and the plasticity of the vestibular system, there is even less clarity regarding if potential vestibular system changes impact functional mobility in a meaningful fashion. This commentary will provide insight as to when we should employ diagnostic vestibular function tests in people with diabetes, where in the periphery we should look, and why testing may or may not matter. The commentary concludes with recommendations for future research and clinical care.

Potential vestibular pathway impairment in children with recurrent vertigo: An investigation through air-conducted sound and galvanic vestibular stimulation-triggered vestibular evoked myogenic potentials.

Objective: This study aims to investigate the potential vestibular pathway impairment through vestibular evoked myogenic potentials (VEMPs) and to explore the pathophysiological significance of these instrument-based findings in children with recurrent vertigo. Materials and methods: The clinical data of 21 children (mean age 4.67 ± 1.39 years) diagnosed as RVC who met the inclusion criteria of the Bárány Society and 29 healthy children (mean age 4.83 ± 1.34 years) enrolled as the control group from February 2021 to December 2021 were collected and analyzed retrospectively. All the subjects underwent both cervical VEMP (cVEMP) and ocular VEMP (oVEMP) triggered by air-conducted sound (ACS) and galvanic vestibular stimulation (GVS), respectively. The elicit rate, latency, and amplitude asymmetry ratio (AAR) of ACS-cVEMP, ACS-oVEMP, GVS-cVEMP, and GVS-oVEMP were analyzed. Results: (1) The elicit rates of ACS-cVEMP and ACS-oVEMP were similar in the two groups (P > 0.05), as well as GVS-cVEMP and GVS-oVEMP (P > 0.05). (2) P1 and N1 latencies of ACS-cVEMP and GVS-cVEMP in the RVC group were longer than those in the control group (P < 0.05). (3) The N1 latency of ACS-oVEMP in the RVC group was shorter than that in the control group (P < 0.05), while there was no significant difference in the P1 latency of ACS-oVEMP (P > 0.05). The N1 and P1 latencies of GVS-oVEMP were not significantly different (P > 0.05). (4) There was no statistical difference in the AAR of ACS-cVEMP and GVS-cVEMP. Although there was an increased AAR of ACS-oVEMP in the RVC group (P < 0.05), the AAR was within the normal range. However, no statistical difference was found in the AAR of GVS-oVEMP in the two groups (P > 0.05). Conclusion: The latencies of ACS-cVEMP and GVS-cVEMP in children with recurrent vertigo were significantly prolonged compared with those in healthy children, and there was no difference in elicit rates of ACS-cVEMP and GVS-cVEMP, suggesting that there might be potential impairment in the inferior vestibular nerve and the subsequent nerve conduction pathway in RVC.

Vestibular and balance function in veterans with chronic dizziness associated with mild traumatic brain injury and blast exposure.

The purpose of this study was to examine vestibular and balance function in individuals with chronic dizziness associated with mTBI/blast. A prospective case-control study design was used to examine ocular motor, vestibular function, and postural stability in veterans with symptoms of dizziness and/or imbalance following an mTBI or blast exposure (n = 77) and a healthy control group (n = 32). Significant group differences were observed for saccadic accuracy, VOR gain during slow harmonic acceleration at 0.01 Hz, cervical vestibular evoked myogenic potentials asymmetry ratio, composite equilibrium score on the sensory organization test, total Dynamic Gait Index score, and gait. The frequency of test abnormalities in participants with mTBI/blast ranged from 0 to 70% across vestibular, ocular motor, and balance/gait testing, with the most frequent abnormalities occurring on tests of balance and gait function. Seventy-two percent of the mTBI/blast participants had abnormal findings on one or more of the balance and gait tests. Vestibular test abnormalities occurred in ~34% of the individuals with chronic dizziness and mTBI/blast, and abnormalities occurred more frequently for measures of otolith organ function (25% for cVEMP and 18% for oVEMP) than for measures of hSCC function (8% for SHA and 6% for caloric test). Abnormal ocular motor function occurred in 18% of the mTBI/blast group. These findings support the need for comprehensive vestibular and balance assessment in individuals with dizziness following mTBI/blast-related injury.

Vestibular Assessment in Patients with Persistent Symptoms of Mild Traumatic Brain Injury.

Aim: The estimated worldwide incidence of TBI is 10 million cases per year. Dizziness and imbalance are two common symptoms in mild TBI (mTBI). In about 10-15% of TBI patients, these symptoms remain for a long time and may show no recovery. These persistent symptoms may relate to different factors including vestibular abnormalities. The aim of this study is a vestibular assessment of patients with persistent symptoms of mTBI by different tests including computerized dynamic posturography. Materials and Methods: 21 patients with mTBI evaluated in this study. Patients were civilians with persistent symptoms. TBI did cause by blunt force trauma (mainly from falling) in the past 6 months. They had normal neurologic and musculoskeletal assessments and no temporal bone fracture. Several auditory and vestibular evaluations were performed for each patient. They included: case history, otoscopy, pure tone and speech audiometry, tympanometry, vestibular bedside examination (spontaneous nystagmus, gaze, saccade, pursuit, Dix-Hallpike maneuver, side-lying maneuver, roll, and Romberg test), cervical Vestibular Myogenic Evoked Potential (c-VEMP), Computerized Dynamic Posturography (CDP) and Dizziness Handicap Inventory (DHI). Results: Patients showed hearing loss in 10 (47.6%) and tinnitus in 4 (19.0%) cases. In ocular motor tests, patients had the most abnormal results in the pursuit test. 6 patients also had Benign Paroxysmal Positional Vertigo (BPPV) in the posterior canal. c-VEMP showed abnormal saccular function in 14 patients. In CDP, the composite scores were decreased relative to normal populations. Conclusion: vestibular tests showed abnormal results in most patients. Vestibular abnormality could relate to persisting symptoms of mTBI patients.

Morphological Fabrication of Equilibrium and Auditory Sensors through Electrolytic Polymerization on Hybrid Fluid Rubber (HF Rubber) for Smart Materials of Robotics.

The development of auditory sensors and systems is essential in smart materials of robotics and is placed at the strategic category of mutual communication between humans and robots. We designed prototypes of the rubber-made equilibrium and auditory sensors, mimicking hair cells in the saccule and the cochlea at the vestibule of the human ear by utilizing our previously proposed technique of electrolytic polymerization on the hybrid fluid rubber (HF rubber). The fabricated artificial hair cells embedded with mimicked free nerve endings and Pacinian corpuscles, which are well-known receptors in the human skin and have already been elucidated effective in the previous study, have the intelligence of equilibrium and auditory sensing. Moreover, they have a voltage that is generated from built-in electricity caused by the ionized particles and molecules in the HF rubber due to piezoelectricity. We verified the equilibrium and auditory characteristics by measuring the changes in voltage with inclination, vibration over a wide frequency range, and sound waves. We elucidated experimentally that the intelligence has optimum morphological conditions. This work has the possibility of advancing the novel technology of state-of-the-art social robotics.

Optimized AAV Vectors for TMC1 Gene Therapy in a Humanized Mouse Model of DFNB7/11.

Gene therapy for genetic hearing loss is an emerging therapeutic modality for hearing restoration. However, the approach has not yet been translated into clinical application. To further develop inner-ear gene therapy, we engineered a novel mouse model bearing a human mutation in the transmembrane channel-1 gene (Tmc1) and characterized the auditory phenotype of the mice. TMC1 forms the mechanosensory transduction channel in mice and humans and is necessary for auditory function. We found that mice harboring the equivalent of the human p.N199I mutation (p.N193I) had profound congenital hearing loss due to loss of hair cell sensory transduction. Next, we optimized and screened viral payloads packaged into AAV9-PHP.B capsids. The vectors were injected into the inner ears of Tmc1Δ/Δ mice and the new humanized Tmc1-p.N193I mouse model. Auditory brainstem responses (ABRs), distortion product otoacoustic emissions (DPOAEs), cell survival, and biodistribution were evaluated in the injected mice. We found broad-spectrum, durable recovery of auditory function in Tmc1-p.N193I mice injected with AAV9-PHP.B-CB6-hTMC1-WPRE. ABR and DPOAE thresholds were equivalent to those of wild-type mice across the entire frequency range. Biodistribution analysis revealed viral DNA/RNA in the contralateral ear, brain, and liver but no overt toxicity. We conclude that the AAV9-PHP.B-CB6-hTMC1-WPRE construct may be suitable for further development as a gene therapy reagent for treatment of humans with genetic hearing loss due to recessive TMC1 mutations.

Indicators of pediatric peripheral vestibular disorder: A retrospective study in a tertiary referral center.

OBJECTIVES: This study aims to present characteristics of pediatric patients with peripheral vertigo and dizziness and their clinical workup results in the tertiary otorhinolaryngology center. We wanted to investigate whether the detailed history could replace the extensive vestibular testing and whether the clinical presentation could guide the first contact physician to appropriately directed specialist referral. METHODS: Retrospective case review of consecutive pediatric vertigo and dizziness patients referred to the tertiary otorhinolaryngology center from 2015 to 2020. The data about the signs and symptoms of vertigo and dizziness and the results of audiological and vestibular tests were collected. RESULTS: Of 257 children aged 10.9±4.3 years (R: 1-17 years), 32 (12.5%) had peripheral, and 49 (19%) had central vertigo and dizziness. Acute vestibulopathy was diagnosed in 22/257 (8.5%) children, sudden sensorineural hearing loss and benign paroxysmal positional vertigo in 5/257 (2%) children each. 60% of children with peripheral vertigo and dizziness had emesis, and 55.6% had nausea. 8% of children had spontaneous horizontal-rotatory nystagmus that followed Alexander's law. Goodman and Kruskal's л for determining whether the type of nystagmus could predict the type of vertigo and dizziness (central or peripheral) was 0.481 (p = 0.001). 12/26 (60%) of children with peripheral vertigo and dizziness had emesis compared to 14 (30.04%) children without emesis, a difference in proportions of 0.296 (p = 0.024, chi-square test of homogeneity). Binomial logistic regression to ascertain the effects of duration, nausea and emesis on the likelihood of the presence of peripheral vertigo was statistically significant (χ2(3) = 10.626, p = 0.014). CONCLUSION: Unlike adults, peripheral vestibular causes of vertigo and dizziness in children may be rare but have the same typical signs and symptoms. The detailed history and careful clinical examination are crucial in differentiating between peripheral and central causes. This guides the first contact physician for further referral to appropriate specialists included in a multidisciplinary workup. Namely, nausea, emesis, horizontal nystagmus and a longer duration of symptoms in a child with vertigo and dizziness indicate a peripheral etiology. Therefore, a referral to an otorhinolaryngologist is reasonable.

Efficient Viral Transduction in Fetal and Adult Human Inner Ear Explants with AAV9-PHP.B Vectors.

Numerous studies have shown the recovery of auditory function in mouse models of genetic hearing loss following AAV gene therapy, yet translation to the clinic has not yet been demonstrated. One limitation has been the lack of human inner ear cell lines or tissues for validating viral gene therapies. Cultured human inner ear tissue could help confirm viral tropism and efficacy for driving exogenous gene expression in targeted cell types, establish promoter efficacy and perhaps selectivity for targeted cells, confirm the expression of therapeutic constructs and the subcellular localization of therapeutic proteins, and address the potential cellular toxicity of vectors or exogenous constructs. To begin to address these questions, we developed an explant culture method using native human inner ear tissue excised at either fetal or adult stages. Inner ear sensory epithelia were cultured for four days and exposed to vectors encoding enhanced green fluorescent protein (eGFP). We focused on the synthetic AAV9-PHP.B capsid, which has been demonstrated to be efficient for driving eGFP expression in the sensory hair cells of mouse and non-human primate inner ears. We report that AAV9-PHP.B also drives eGFP expression in fetal cochlear hair cells and in fetal and adult vestibular hair cells in explants of human inner ear sensory epithelia, which suggests that both the experimental paradigm and the viral capsid may be valuable for translation to clinical application.