Single-cell transcriptomic atlas reveals increased regeneration in diseased human inner ear balance organs.

Mammalian inner ear hair cell loss leads to permanent hearing and balance dysfunction. In contrast to the cochlea, vestibular hair cells of the murine utricle have some regenerative capacity. Whether human utricular hair cells regenerate in vivo remains unknown. Here we procured live, mature utricles from organ donors and vestibular schwannoma patients, and present a validated single-cell transcriptomic atlas at unprecedented resolution. We describe markers of 13 sensory and non-sensory cell types, with partial overlap and correlation between transcriptomes of human and mouse hair cells and supporting cells. We further uncover transcriptomes unique to hair cell precursors, which are unexpectedly 14-fold more abundant in vestibular schwannoma utricles, demonstrating the existence of ongoing regeneration in humans. Lastly, supporting cell-to-hair cell trajectory analysis revealed 5 distinct patterns of dynamic gene expression and associated pathways, including Wnt and IGF-1 signaling. Our dataset constitutes a foundational resource, accessible via a web-based interface, serving to advance knowledge of the normal and diseased human inner ear.

Traumatic Events Preceding the Development of Superior Canal Dehiscence Syndrome.

OBJECTIVE: To describe the features of antecedent head trauma in patients with superior canal dehiscence syndrome (SCDS). STUDY DESIGN: Cross-sectional survey. SETTING: Tertiary referral center. METHODS: An online survey was sent to 450 adult patients who underwent surgical repair for SCDS patients asking questions about the nature of internal or external traumatic events preceding symptoms. RESULTS: One-hundred and thirty-six patients (avg. age, 51.9 years, 62.8% female) completed the survey, of which 61 (44.9%) described either preceding external head trauma (n = 35, 26%), preceding internal pressure event (n = 33, 25%), or both (8, 6%). Of those endorsing external trauma, 22 (63%) described a singular event (head hit by object (n = 8); head hit ground (n = 5); motor vehicle accident (n = 4); assault (n = 2); other (n = 3). One-third experienced loss of consciousness because of the trauma. For those describing internal pressure events (n = 33), the most common events were heavy physical exertion (9, 27%); pressure changes while flying (6, 18%); coughing, nose blowing with illness (5, 15%); childbirth (5, 15%); and self contained underwater breathing apparatus diving events (3, 9%). The interval between trauma and onset of symptoms averaged 5.6 years (SD, 10.7 years). One-third (n = 19) described onset of symptoms immediately after the external trauma or internal pressure event. Symptoms began on the side ipsilateral to the trauma in 91%. Sound- and pressure-induced vertigo/oscillopsia developed more commonly after external trauma versus internal pressure events (68% and 61% vs 44% and 32%, respectively). CONCLUSION: Trauma or internal pressure-related events precede SCDS symptoms in nearly half of cases, with roughly half of preceding events being external.

Sensory and motor deficits as contributors to early cognitive impairment.

INTRODUCTION: Age-related sensory and motor impairment are associated with risk of dementia. No study has examined the joint associations of multiple sensory and motor measures on prevalence of early cognitive impairment (ECI). METHODS: Six hundred fifty participants in the Baltimore Longitudinal Study of Aging completed sensory and motor function tests. The association between sensory and motor function and ECI was examined using structural equation modeling with three latent factors corresponding to multisensory, fine motor, and gross motor function. RESULTS: The multisensory, fine, and gross motor factors were all correlated (r = 0.74 to 0.81). The odds of ECI were lower for each additional unit improvement in the multisensory (32%), fine motor (30%), and gross motor factors (12%). DISCUSSION: The relationship between sensory and motor impairment and emerging cognitive impairment may guide future intervention studies aimed at preventing and/or treating ECI. HIGHLIGHTS: Sensorimotor function and early cognitive impairment (ECI) prevalence were assessed via structural equation modeling. The degree of fine and gross motor function is associated with indicators of ECI. The degree of multisensory impairment is also associated with indicators of ECI.

Local spatial navigation or "steering" in patients with vestibular loss in a virtual reality environment.

BACKGROUND: Patients with vestibular loss have reduced wayfinding ability, but the association between vestibular loss and impaired steering spatial navigation is unclear. OBJECTIVE: To evaluate whether vestibular loss is associated with reduced steering navigation performance in a virtual reality (VR) environment containing obstacles. METHODS: 17 ambulatory adults with vestibular loss were age/sex-matched to healthy controls. Participants traversed a VR hallway with obstacles, and their navigation performance was compared using metrics such as collisions, time, total distance travelled, and speed in single and multivariate analysis. RESULTS: In univariate analysis there was no significant difference in collisions between vestibular patients and controls (1.84 vs. 2.24, p = 0.974). However, vestibular patients took more time, longer routes, and had lower speeds to complete the task (56.9 vs. 43.9 seconds, p < 0.001; 23.1 vs. 22.0 meters, p = 0.0312; 0.417 vs. 0.544 m/s, p < 0.001). These results were confirmed in multivariate analysis. CONCLUSIONS: This study found that patients with vestibular loss displayed slower gait speeds and traveled longer distances, though did not make more collisions, during a VR steering navigation task. Beyond the known influence of vestibular function on gait speed, vestibular loss may also contribute to less efficient steering navigation through an obstacle-laden environment, through neural mechanisms that remain to be elucidated.

Association Between Retinal Pathology and Hearing in Older Adults.

We investigated the association between retinal microvascular changes and hearing loss based on the hypothesis that both may result from shared microvascular pathology. Data from 536 older adults from the National Health and Nutritional Examination Survey 2005 to 2006 including sociodemographic and health characteristics, pure-tone hearing thresholds, and retinal pathologies were collected and analyzed. Associations between retinal and hearing pathologies were modeled with multivariable-adjusted linear regressions. 75% of participants had hearing loss and 15% of participants had retinopathy. The association between retinopathy, microaneurysms, and blot hemorrhages with better speech-frequency pure tone average was -2.81 (95% confidence interval [CI]: -5.72 to 0.10), -4.75 (95% CI: -8.73 to -0.78), and -5.34 (95% CI: -8.68 to -2.00), respectively. The presence of retinopathy, microaneurysms, and blot hemorrhages was inversely associated with hearing loss. Further studies are needed to better understand the potential relationship between microvascular pathologies of the eye and ear.

Acoustic Noise Levels in High-field Magnetic Resonance Imaging Scanners.

7-Tesla (T) magnetic resonance imaging may allow for higher resolution images but may produce greater acoustic noise than 1.5- and 3-T scanners. We sought to characterize the intensity of acoustic noise from 7- versus 3-T scanners. A-weighted sound pressure levels from 5 types of pulse sequences used for brain and inner ear imaging in 3- and 7-T scanners were measured. Time-averaged sound level and maximum sound levels generated for each sequence were compared. Time-averaged sound levels exceeded 95 dB and reached maximums above 105 dB on the majority of 3- and 7-T scans. The mean time-averaged sound level and maximum sound level across pulse sequences were greater in 7- than 3-T (105.6 vs 91.4, P = .01; 114.0 vs. 96.5 dB, P < .01). 7- and 3-T magnetic resonance imaging scanners produce high levels of acoustic noise that exceed acceptable safety limits, emphasizing the need for active and passive noise protection.

Longitudinal Auditory Benefit for Elderly Patients After Cochlear Implant for Bilateral Hearing Loss, Including Those Meeting Expanded Centers for Medicare & Medicaid Services Criteria.

OBJECTIVE: To examine the effect of patient age on longitudinal speech understanding outcomes after cochlear implantation (CI) in bilateral hearing loss. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary academic center. PATIENTS: One thousand one hundred five adult patients with bilateral hearing loss receiving a unilateral CI between 1987 and 2022InterventionsNone. MAIN OUTCOME MEASURES: Postoperative speech recognition outcomes, including AzBio sentences, consonant-nucleus-consonant word, and Hearing in Noise Test in quiet were analyzed at short-term (<2 yr), medium-term (2-8 y), and long-term (>8 yr) term postoperative intervals. RESULTS: Eighty-six very elderly (>80 yr), 409 elderly (65-80 yr), and 709 nonelderly (18-65 yr) patients were included. Short-term postoperative AzBio scores demonstrated similar magnitude of improvement relative to preoperative scores in the very elderly (47.6, 95% confidence interval [CI], 28.9-66.4), elderly (49.0; 95% CI, 39.2-58.8), and nonelderly (47.9; 95% CI, 35.4-60.4). Scores for those older than 80 years remained stable after 2 years after implant, but in those 80 years or younger, scores continued to improve for up to 8 years (elderly: 6.2 [95% CI, 1.5-12.4]; nonelderly: 9.9 [95% CI, 2.1-17.7]) after implantation. Similar patterns were observed for consonant-nucleus-consonant word scores. Across all age cohorts, patients with preoperative Hearing in Noise Test scores between 40 and 60% had similar scores to those with preoperative scores of less than 40%, at short-term (82.4, 78.9; 95% CI, -23.1 to 10.0), medium-term (77.2, 83.9; 95% CI, -15.4 to 8.2), or long-term (73.4, 71.2; 95% CI, -18.2 to 12.2) follow-up. CONCLUSIONS: Patients older than 80 years gain significant and sustained auditory benefit after CI, including those meeting expanded Centers for Medicare & Medicaid Service criteria for implantation. Patients younger than 80 years demonstrated continued improvement over longer periods than older patients, suggesting a role of central plasticity in mediating CI outcomes as a function of age.

Natural History of Cystic Vestibular Schwannomas.

OBJECTIVE: To determine the natural history of cystic vestibular schwannomas (VS). STUDY DESIGN: Retrospective cohort. SETTING: Single tertiary academic hospital. PATIENTS: Adults diagnosed with cystic VS who had at least 2 MRIs performed at least 6 months apart between 2008 and 2016 with no intervening treatment. MAIN OUTCOME MEASURES: Volumetric growth rates of both the entire tumor and individual cystic and solid components were measured. Linear growth rate of the entire tumor was assessed using the largest diameter parallel to the petrous face at the cerebellopontine angle (CPA). RESULTS: Twenty-one patients met inclusion criteria. The average volumetric growth rate of the tumor was 1.1 ± 2 (range: -1.2 to 7.8), while the average growth rate of the cystic component was 0.8 ± 1.6 (range: -0.5 to 5.3) cm3/year. The CPA diameter of the tumor demonstrated an average linear growth rate of was 1.2 ± 4.4 (range: -8to 13.5) mm/year. With regards to tumor diameter, 9/21 (42.9%) remained stable, 3/21 (14.2%) decreased in size, while 9/21 (42.9%) increased in size. CONCLUSIONS: Cystic tumors demonstrate a wide variability in growth rate. Larger, multi-center studies will be required to further compare this relationship to solid tumors.

Repair of surviving hair cells in the damaged mouse utricle.

Sensory hair cells (HCs) in the utricle are mechanoreceptors required to detect linear acceleration. After damage, the mammalian utricle partially restores the HC population and organ function, although regenerated HCs are primarily type II and immature. Whether native, surviving HCs can repair and contribute to this recovery is unclear. Here, we generated the Pou4f3DTR/+; Atoh1CreERTM/+; Rosa26RtdTomato/+ mouse to fate map HCs prior to ablation. After HC ablation, vestibular evoked potentials were abolished in all animals, with ∼57% later recovering responses. Relative to nonrecovery mice, recovery animals harbored more Atoh1-tdTomato+ surviving HCs. In both groups, surviving HCs displayed markers of both type I and type II subtypes and afferent synapses, despite distorted lamination and morphology. Surviving type II HCs remained innervated in both groups, whereas surviving type I HCs first lacked and later regained calyces in the recovery, but not the nonrecovery, group. Finally, surviving HCs initially displayed immature and subsequently mature-appearing bundles in the recovery group. These results demonstrate that surviving HCs are capable of self-repair and may contribute to the recovery of vestibular function.

Assessment of auditory and vestibular damage in a mouse model after single and triple blast exposures.

The use of explosive devices in war and terrorism has increased exposure to concussive blasts among both military personnel and civilians, which can cause permanent hearing and balance deficits that adversely affect survivors' quality of life. Significant knowledge gaps on the underlying etiology of blast-induced hearing loss and balance disorders remain, especially with regard to the effect of blast exposure on the vestibular system, the impact of multiple blast exposures, and long-term recovery. To address this, we investigated the effects of blast exposure on the inner ear using a mouse model in conjunction with a high-fidelity blast simulator. Anesthetized animals were subjected to single or triple blast exposures, and physiological measurements and tissue were collected over the course of recovery for up to 180 days. Auditory brainstem responses (ABRs) indicated significantly elevated thresholds across multiple frequencies. Limited recovery was observed at low frequencies in single-blasted mice. Distortion Product Otoacoustic Emissions (DPOAEs) were initially absent in all blast-exposed mice, but low-amplitude DPOAEs could be detected at low frequencies in some single-blast mice by 30 days post-blast, and in some triple-blast mice at 180 days post-blast. All blast-exposed mice showed signs of Tympanic Membrane (TM) rupture immediately following exposure and loss of outer hair cells (OHCs) in the basal cochlear turn. In contrast, the number of Inner Hair Cells (IHCs) and spiral ganglion neurons was unchanged following blast-exposure. A significant reduction in IHC pre-synaptic puncta was observed in the upper turns of blast-exposed cochleae. Finally, we found no significant loss of utricular hair cells or changes in vestibular function as assessed by vestibular evoked potentials. Our results suggest that (1) blast exposure can cause severe, long-term hearing loss which may be partially due to slow TM healing or altered mechanical properties of healed TMs, (2) traumatic levels of sound can still reach the inner ear and cause basal OHC loss despite middle ear dysfunction caused by TM rupture, (3) blast exposure may result in synaptopathy in humans, and (4) balance deficits after blast exposure may be primarily due to traumatic brain injury, rather than damage to the peripheral vestibular system.

Canalplasty for Exostosis Removal Comparing Microscopic Versus Endoscopic Ear Surgery Techniques.

OBJECTIVE: To compare an endoscopic versus microscopic approach to removal of exostoses and osteomas in canalplasty procedures. STUDY DESIGN: Retrospective case review. SETTING: Private and tertiary referral centers. PATIENTS: Adult patients requiring canalplasty procedures performed either microscopically or endoscopically for removal of exostosis or osteoma and/or canal stenosis. INTERVENTION: Microscopic or endoscopic canalplasty. MAIN OUTCOME MEASURE: Major outcome measures included assessment of hearing improvement as well as rates of major and minor complications. Standard audiological data were collected before and after the operative procedure. Major complications queried included stenosis, perforation of the tympanic membrane, hearing loss, facial palsy, and osteomyelitis. Minor complications queried included signs of poor wound healing, graft failure, and bleeding or discharge. RESULTS: Forty three canalplasties were performed on 36 patients. Audiometric tests did not significantly differ between endoscopic and microscopic surgeries. There was a moderate linear relationship between date of surgery and duration of surgery for the endoscopic technique, with more recent surgeries taking less time. No major complications were noted. However, significantly fewer endoscopic cases had evidence of minor postoperative complications relative to microscopic cases. CONCLUSIONS: An endoscopic approach to canalplasty is a safe and minimally invasive technique. Significantly fewer postoperative complications occurred after endoscopic canalplasty procedures as compared with microscopic procedures. Endoscopic repair may be preferred to microscopic repairs due to the improved view of the end of the instruments while maintaining a minimally invasive approach with what is likely a decreased operative time as well.

Modeling drug response using network-based personalized treatment prediction (NetPTP) with applications to inflammatory bowel disease.

For many prevalent complex diseases, treatment regimens are frequently ineffective. For example, despite multiple available immunomodulators and immunosuppressants, inflammatory bowel disease (IBD) remains difficult to treat. Heterogeneity in the disease across patients makes it challenging to select the optimal treatment regimens, and some patients do not respond to any of the existing treatment choices. Drug repurposing strategies for IBD have had limited clinical success and have not typically offered individualized patient-level treatment recommendations. In this work, we present NetPTP, a Network-based Personalized Treatment Prediction framework which models measured drug effects from gene expression data and applies them to patient samples to generate personalized ranked treatment lists. To accomplish this, we combine publicly available network, drug target, and drug effect data to generate treatment rankings using patient data. These ranked lists can then be used to prioritize existing treatments and discover new therapies for individual patients. We demonstrate how NetPTP captures and models drug effects, and we apply our framework to individual IBD samples to provide novel insights into IBD treatment.

Congenital Hearing Loss Is Associated With a High Incidence of Central Nervous System Abnormalities.

OBJECTIVE(S): To assess the incidence of central nervous system abnormalities in pediatric subjects with sensorineural hearing loss (SNHL). METHODS: One hundred forty-three pediatric subjects evaluated for SNHL at a single academic center from 2007 to 2014 were included and divided into eight diagnosis groups based on etiology of SNHL. One hundred forty-three age- and gender-matched control subjects with no known brain-related pathology or history of hearing loss were included as healthy controls for comparison. Two neuroradiologists independently evaluated magnetic resonance imaging (MRI) and computed tomography (CT) scans for each subject. Comparison of abnormal cerebral development was performed using an ordinal logistic regression model. Concordance between CT and MRI of the temporal bone was assessed using the kappa statistic. RESULTS: The etiologies of hearing loss in our cohort were 37.8% genetic, 12.6% infectious, 1.4% ototoxin-induced, and 48.3% idiopathic. Brain MRI revealed cerebral developmental abnormalities in defined regions in >30% of the SNHL cohort, significantly more than in normal-hearing pediatric controls. The Sylvian fissure, Virchow-Robin spaces, and lateral ventricles were most commonly affected. In the temporal bone, the percentage of subjects with concordant findings on CT and MRI was ≥92% across all anatomical structures. CONCLUSION: MRI revealed a high incidence of intracranial abnormalities, suggestive of aberrant development of auditory and nonauditory neural structures associated with SNHL. CT and MRI share a high degree of concordance in detecting temporal bone anomalies. Inclusion of MRI as part of the workup of congenital SNHL may facilitate the detection of developmental anomalies of the brain associated with SNHL.

Ambient Pressure Tympanometry Wave Patterns in Patients With Superior Semicircular Canal Dehiscence.

Importance: Superior semicircular canal dehiscence (SSCD) is a treatable condition, but current diagnostic modalities have numerous limitations. Clinicians would benefit from an additional tool for diagnostic workup that is both rapid and widely available. Objective: To assess the utility of ambient pressure tympanometry (APT) in the diagnostic workup of SSCD by determining the sensitivity and specificity of APT for SSCD in comparison to other diagnostic modalities. Design: Retrospective cohort study of patients who underwent APT and temporal bone computerized tomography (CT) scans from May 2017 to July 2018. Setting: Tertiary referral center. Participants: APT was performed as part of routine audiological testing on adult patients. We retrospectively analyzed all patients who received both APT and temporal bone CT scans, and divided ears into SSCD and non-SSCD groups based on the presence or absence of radiographic SSCD. Ears with other radiographic findings that could affect tympanic membrane compliance were excluded. Exposures: All patients in this study underwent APT and temporal bone CT scans. Some patients also underwent pure tone audiometry and vestibular evoked myogenic potentials (VEMPs). Main Outcomes and Measures: The primary outcome measures were sensitivity, specificity, and risk ratio of APT for SSCD. Secondary outcome measures include sensitivity of VEMPs and supranormal hearing thresholds. Results: We describe 52 patients (70 ears) who underwent APT and CT imaging (mean age 47.1 years, 67.1% female). APT detected SSCD with 66.7% sensitivity and 72.1% specificity. In symptomatic patients, sensitivity was 71.4% and specificity was 75%. VEMPs performed best at detecting SSCD when defining a positive test as oVEMP amplitude >17 µV, with a sensitivity of 68.2%, similar to APT (p > 0.99). The combination of APT and VEMPs increased sensitivity to 88.9%, better than APT alone (p = 0.031) and trending toward better than VEMPs alone (p = 0.063). Conclusions and Relevance: Rhythmic wave patterns on APT are associated with SSCD and may raise suspicion for this condition in conjunction with consistent results on other diagnostic modalities. Although clinical utility requires confirmation in a larger prospective study, APT is a simple, rapid, and widely available tool warranting further study.

Rhythmic Wave Patterns on Ambient Pressure Tympanometry in Patients With Objective Tinnitus-associated Pathologies.

OBJECTIVE: To introduce the concept of ambient pressure tympanometry (APT) and its association with pathologies that may present with objective tinnitus. STUDY DESIGN: Retrospective case series. SETTING: Tertiary referral center. SUBJECTS AND METHODS: Audiologists performed APT on adult patients as part of routine audiological testing. Ears with myoclonus and patulous Eustachian tube (PET) were identified via review of patient history and physical examination. All other conditions were verified via computed tomography (CT) temporal bone imaging. Ears with conditions that could impair tympanic membrane compliance, such as otosclerosis or tympanic membrane perforation, were excluded. APT findings were analyzed via a novel algorithm. RESULTS: A radiographic finding associated with objective tinnitus was confirmed in 67 ears that underwent CT imaging; 45 (67%) of these ears displayed rhythmic APT wave patterns. These included 28 ears with superior semicircular canal dehiscence, 4 ears with sigmoid sinus dehiscence, 6 ears with internal carotid artery dehiscence, 4 ears with glomus tumor, and 3 ears with encephalocele. In addition, we identified three ears with myoclonus and one ear with PET. In a subset of 30 ears with objective tinnitus symptoms that underwent CT imaging, 22 displayed rhythmic waves; of these 22 ears, 20 (91%) had a radiographic finding associated with objective tinnitus. CONCLUSIONS: Rhythmic APT wave patterns are common and may be associated with numerous temporal bone pathologies that may present with objective tinnitus. APT is a simple, rapid, and widely available tool that warrants further study to determine its value in screening of these otologic conditions.

Application-Based Translaryngeal Ultrasound for the Assessment of Vocal Fold Mobility in Children.

OBJECTIVE: To compare the evaluation of vocal fold mobility between flexible nasal laryngoscopy (FNL) and a handheld application-based translaryngeal ultrasound (TLUS) platform. STUDY DESIGN: Prospective analysis included patients with unknown vocal fold mobility status who underwent FNL and TLUS. SETTING: Tertiary referral center. SUBJECTS AND METHODS: TLUS was performed on 23 consecutive children (<18 years old) presenting for laryngoscopy due to unknown vocal fold mobility status. After the recording of three 10-second TLUS videos as well as FNL, the study was divided into 2 parts: parental assessment of laryngeal ultrasound at the time of patient evaluation and random practitioner assessment of ultrasound videos. RESULTS: We describe 23 patients who underwent TLUS and FNL. Ten patients (43.5%) had normal vocal fold function bilaterally, and 13 (56.5%) had either left or right vocal fold immobility. Family members and physicians correctly identified the presence and laterality of impaired vocal fold mobility in 22 of 23 cases (κ = 0.96). The sensitivity, specificity, positive predictive value, and negative predictive value of FLUS in diagnosing vocal fold immobility were 92.3%, 100%, 100%, and 90.9%, respectively. Random practitioners accurately identified the presence and laterality of vocal fold immobility under all circumstances. CONCLUSION: A handheld application-based ultrasound platform is both sensitive and specific in its ability to identify vocal fold motion impairment. Portable handheld TLUS has the potential to serve as a validated screening examination, even by inexperienced providers, and in specific cases may obviate the need for an invasive transnasal laryngoscopy.

Uncoordinated maturation of developing and regenerating postnatal mammalian vestibular hair cells.

Sensory hair cells are mechanoreceptors required for hearing and balance functions. From embryonic development, hair cells acquire apical stereociliary bundles for mechanosensation, basolateral ion channels that shape receptor potential, and synaptic contacts for conveying information centrally. These key maturation steps are sequential and presumed coupled; however, whether hair cells emerging postnatally mature similarly is unknown. Here, we show that in vivo postnatally generated and regenerated hair cells in the utricle, a vestibular organ detecting linear acceleration, acquired some mature somatic features but hair bundles appeared nonfunctional and short. The utricle consists of two hair cell subtypes with distinct morphological, electrophysiological and synaptic features. In both the undamaged and damaged utricle, fate-mapping and electrophysiology experiments showed that Plp1+ supporting cells took on type II hair cell properties based on molecular markers, basolateral conductances and synaptic properties yet stereociliary bundles were absent, or small and nonfunctional. By contrast, Lgr5+ supporting cells regenerated hair cells with type I and II properties, representing a distinct hair cell precursor subtype. Lastly, direct physiological measurements showed that utricular function abolished by damage was partially regained during regeneration. Together, our data reveal a previously unrecognized aberrant maturation program for hair cells generated and regenerated postnatally and may have broad implications for inner ear regenerative therapies.