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.

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.

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.

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.

Sensory hair cell development and regeneration: similarities and differences.

Sensory hair cells are mechanoreceptors of the auditory and vestibular systems and are crucial for hearing and balance. In adult mammals, auditory hair cells are unable to regenerate, and damage to these cells results in permanent hearing loss. By contrast, hair cells in the chick cochlea and the zebrafish lateral line are able to regenerate, prompting studies into the signaling pathways, morphogen gradients and transcription factors that regulate hair cell development and regeneration in various species. Here, we review these findings and discuss how various signaling pathways and factors function to modulate sensory hair cell development and regeneration. By comparing and contrasting development and regeneration, we also highlight the utility and limitations of using defined developmental cues to drive mammalian hair cell regeneration.

One Month of Oral Morphine Decreases Gray Matter Volume in the Right Amygdala of Individuals with Low Back Pain: Confirmation of Previously Reported Magnetic Resonance Imaging Results.

OBJECTIVE: Prolonged exposure to opioids is known to produce neuroplastic changes in animals; however, few studies have investigated the effects of short-term prescription opioid use in humans. A previous study from our laboratory demonstrated a dosage-correlated volumetric decrease in the right amygdala of participants administered oral morphine daily for 1 month. The purpose of this current study was to replicate and extend the initial findings. METHODS: Twenty-one participants with chronic low back pain were enrolled in this double-blind, placebo-controlled study. Participants were randomized to receive daily morphine (n = 11) or a matched placebo (n = 10) for 1 month. High-resolution anatomical images were acquired immediately before and after the treatment administration period. Morphological gray matter changes were investigated using tensor-based morphometry, and significant regions were subsequently tested for correlation with morphine dosage. RESULTS: Decreased gray matter volume was observed in several reward- and pain-related regions in the morphine group, including the bilateral amygdala, left inferior orbitofrontal cortex, and bilateral pre-supplementary motor areas. Morphine administration was also associated with significant gray matter increases in cingulate regions, including the mid cingulate, dorsal anterior cingulate, and ventral posterior cingulate. CONCLUSIONS: Many of the volumetric increases and decreases overlapped spatially with the previously reported changes. Individuals taking placebo for 1 month showed neither gray matter increases nor decreases. The results corroborate previous reports that rapid alterations occur in reward-related networks following short-term prescription opioid use.

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.

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.

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.

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.

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.

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.

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.

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.

Atoh1 Directs Regeneration and Functional Recovery of the Mature Mouse Vestibular System.

Utricular hair cells (HCs) are mechanoreceptors required for vestibular function. After damage, regeneration of mammalian utricular HCs is limited and regenerated HCs appear immature. Thus, loss of vestibular function is presumed irreversible. Here, we found partial HC replacement and functional recovery in the mature mouse utricle, both enhanced by overexpressing the transcription factor Atoh1. Following damage, long-term fate mapping revealed that support cells non-mitotically and modestly regenerated HCs displaying no or immature bundles. By contrast, Atoh1 overexpression stimulated proliferation and widespread regeneration of HCs exhibiting elongated bundles, patent mechanotransduction channels, and synaptic connections. Finally, although damage without Atoh1 overexpression failed to initiate or sustain a spontaneous functional recovery, Atoh1 overexpression significantly enhanced both the degree and percentage of animals exhibiting sustained functional recovery. Therefore, the mature, damaged utricle has an Atoh1-responsive regenerative program leading to functional recovery, underscoring the potential of a reprogramming approach to sensory regeneration.

Molecular therapy for genetic and degenerative vestibular disorders.

PURPOSE OF REVIEW: The primary purpose of this review is to summarize current literature in the field of vestibular regeneration with a focus on recent developments in molecular and gene therapies. RECENT FINDINGS: Since the discovery of limited vestibular hair cell regeneration in mammals in the 1990s, many elegant studies have improved our knowledge of mechanisms of development and regeneration of the vestibular system. A better understanding of the developmental pathways of the vestibular organs has fueled various biological strategies to enhance regeneration, including novel techniques in deriving vestibular hair cells from embryonic and induced pluripotent stem cells. In addition, the identification of specific genetic mutations responsible for vestibular disorders has opened various opportunities for gene replacement therapy. SUMMARY: Vestibular dysfunction is a significant clinical problem with limited therapeutic options, warranting research on biological strategies to repair/regenerate the vestibular organs to restore function. The use of gene therapy appears promising in animal models of vestibular dysfunction.