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Objectives. Balloon dilation of the Eustachian tube (BDET) is widely recognized as a minimally invasive treatment for obstructive Eustachian tube dysfunction (ETD). We employed a Delphi consensus methodology to develop recommendations for the clinical management of BDET in cases of obstructive ETD. Methods. A Delphi panel consisting of 26 expert physicians specializing in otology participated in two rounds of anonymous, iterative questionnaires. Consensus was defined as agreement from ≥70% of the panelists on a recommendation, while disagreement was defined as

Abstract Advances in next-generation sequencing technologies have led to elucidation of sensorineural hearing loss genetics and associated clinical impacts. However, studies on the functional pathogenicity of variants of uncertain significance (VUS), despite their close association with clinical phenotypes, are lacking. Here we identified compound heterozygous variants in ESRRB transcription factor gene linked to DFNB35, specifically a novel splicing variant (NM_004452.4(ESRRB): c.397 + 2T>G) in trans with a missense variant (NM_004452.4(ESRRB): c.1144C>T p.(Arg382Cys)) whose pathogenicity remains unclear. The splicing variant (c.397 + 2T>G) caused exon 4 skipping, leading to premature stop codon formation and nonsense-mediated decay. The p.(Arg382Cys) variant was classified as a VUS due to its particularly higher allele frequency among East Asian population despite disease-causing in-silico predictions. However, functional assays showed that p.(Arg382Cys) variant disrupted key intramolecular interactions, leading to protein instability. This variant also reduced transcriptional activity and altered expression of downstream target genes essential for inner ear function, suggesting genetic contribution to disease phenotype. This study expanded the phenotypic and genotypic spectrum of ESRRB in DFNB35 and revealed molecular mechanisms underlying ESRRB-associated DFNB35. These findings suggest that variants with high allele frequencies can also possess functional pathogenicity, providing a breakthrough for cases where VUS, previously unexplored, could be reinterpreted by elucidating their functional roles and disease-causing characteristics.

BACKGROUND:Peripheral auditory deafferentation and central compensation have been regarded as the main culprits of tinnitus generation. However, patient-to-patient discrepancy in the range of the percentage of daytime in which tinnitus is perceived (tinnitus awareness percentage, 0 - 100%), is not fully explicable only by peripheral deafferentation, considering that the deafferentation is a stable persisting phenomenon but tinnitus is intermittently perceived in most patients. Consequently, the involvement of a dysfunctional noise cancellation mechanism has recently been suggested with regard to the individual differences in reported tinnitus awareness. By correlating the tinnitus awareness percentage with resting-state source-localized electroencephalography findings, we may be able to retrieve the cortical area that is negatively correlated with tinnitus awareness percentage, and then the area may be regarded as the core of the noise cancelling system that is defective in patients with tinnitus. METHODS AND FINDINGS:Using resting-state cortical oscillation, we investigated 80 tinnitus patients by correlating the tinnitus awareness percentage with their source-localized cortical oscillatory activity and functional connectivity. The activity of bilateral rostral anterior cingulate cortices (ACCs), left dorsal- and pregenual ACCs for the delta band, bilateral rostral/pregenual/subgenual ACCs for the theta band, and left rostral/pregenual ACC for the beta 1 band displayed significantly negative correlations with tinnitus awareness percentage. Also, the connectivity between the left primary auditory cortex (A1) and the rostral ACC, as well as between the left A1 and the subgenual ACC for the beta 1 band, were negatively correlated with tinnitus awareness percentage. CONCLUSIONS:These results may designate the role of the rostral ACC as the core of the descending noise cancellation system, and thus dysfunction of the rostral ACC may result in perception of tinnitus. The present study also opens a possibility of tinnitus modulation by neuromodulatory approaches targeting the rostral ACC.

Research indicates that hearing loss significantly contributes to tinnitus, but it alone does not fully explain its occurrence, as many people with hearing loss do not experience tinnitus. To identify a secondary factor for tinnitus generation, we examined a unique dataset of individuals with intermittent chronic tinnitus, who experience fluctuating periods of tinnitus. EEGs of healthy controls were compared to EEGs of participants who reported perceiving tinnitus on certain days, but no tinnitus on other days.. The EEG data revealed that tinnitus onset is associated with increased theta activity in the pregenual anterior cingulate cortex and decreased theta functional connectivity between the pregenual anterior cingulate cortex and the auditory cortex. Additionally, there is increased alpha effective connectivity from the dorsal anterior cingulate cortex to the pregenual anterior cingulate cortex. When tinnitus is not perceived, differences from healthy controls include increased alpha activity in the pregenual anterior cingulate cortex and heightened alpha connectivity between the pregenual anterior cingulate cortex and auditory cortex. This suggests that tinnitus is triggered by a switch involving increased theta activity in the pregenual anterior cingulate cortex and decreased theta connectivity between the pregenual anterior cingulate cortex and auditory cortex, leading to increased theta-gamma cross-frequency coupling, which correlates with tinnitus loudness. Increased alpha activity in the dorsal anterior cingulate cortex correlates with distress. Conversely, increased alpha activity in the pregenual anterior cingulate cortex can transiently suppress the phantom sound by enhancing theta connectivity to the auditory cortex. This mechanism parallels chronic neuropathic pain and suggests potential treatments for tinnitus by promoting alpha activity in the pregenual anterior cingulate cortex and reducing alpha activity in the dorsal anterior cingulate cortex through pharmacological or neuromodulatory approaches.

Pathogenic structure variations (SVs) are associated with various types of cancer and rare genetic diseases. Recent studies have used Cas9 nuclease with paired guide RNAs (gRNAs) to generate targeted chromosomal rearrangements, focusing on producing fusion proteins that cause cancer, whereas research on precision genome editing for rectifying SVs is limited. In this study, we identified a novel complex genomic rearrangement (CGR), specifically an EYA1 inversion with a deletion, implicated in branchio-oto-renal/branchio-oto syndrome. To address this, two CRISPR-based approaches were tested. First, we used Cas9 nuclease and paired gRNAs tailored to the patient’s genome. The dual CRISPR-Cas9 system induced efficient correction of paracentric inversion in patient-derived fibroblast, and effectively restored the expression of EYA1 mRNA and protein, along with its transcriptional activity required to regulate the target gene expression. Additionally, we used CRISPR activation (CRISPRa), which leads to the upregulation of EYA1 mRNA expression in patient-derived fibroblasts. Moreover, CRISPRa significantly improved EYA1 protein expression and transcriptional activity essential for target gene expression. This suggests that CRISPRa-based gene therapies could offer substantial translational potential for approximately 70% of disease-causing EYA1 variants responsible for haploinsufficiency. Our findings demonstrate the potential of CRISPR-guided genome editing for correcting SVs, including those with EYA1 CGR linked to haploinsufficiency.

Abstract Branchio-oto-renal (BOR)/branchio-otic (BO) syndrome is a rare disorder and exhibits clinically heterogenous phenotypes, marked by abnormalities in the ear, branchial arch, and renal system. Sporadic cases of atypical BOR/BO syndrome have been recently reported; however, evidence on genotype–phenotype correlations and molecular mechanisms of those cases is lacking. We herein identified five SIX1 heterozygous variants (c.307dupC:p.Leu103Profs*51, c.373G>A:p.Glu125Lys, c.386_391del:p.Tyr129_Cys130del, c.397_399del:p.Glu133del, and c.501G>C:p.Gln167His), including three novel variants, through whole-exome sequencing in five unrelated Korean families. All eight affected individuals with SIX1 variants displayed non-syndromic hearing loss (DFNA23) or atypical BO syndrome. The prevalence of major and minor criteria for BOR/BO syndrome was significantly reduced among individuals with SIX1 variants, compared to 15 BOR/BO syndrome families with EYA1 variants. All SIX1 variants interacted with the EYA1 wild-type; their complexes were localized in the nucleus except for the p.Leu103Profs*51 variant. All mutants also showed obvious but varying degrees of reduction in DNA binding affinity, leading to a significant decrease in transcriptional activity. This study presents the first report of SIX1 variants in South Korea, expanding the genotypic and phenotypic spectrum of SIX1 variants, characterized by DFNA23 or atypical BO syndrome, and refines the diverse molecular aspects of SIX1 variants according to the EYA1–SIX1–DNA complex theory.

Background and purposeCustomized vestibular rehabilitation improved dizziness and imbalance in several randomized controlled trials. In the present study, we determined the efficacy of customized vestibular rehabilitation using real-world observational data.MethodsIn this retrospective observational study, we recruited 64 patients (median age = 60, interquartile range = 48–66.3) who completed the customized vestibular rehabilitation from January to December 2022. The outcomes of rehabilitation were evaluated using the dizziness handicap inventory (DHI) or vestibular disorders activities of daily living scale (VADL). The factors associated with outcomes were assessed with a generalized linear model, of which covariates included patients’ age, sex, duration of illness, type of vestibular disorders, initial DHI and VADL scores, exercise compliance, and initial hospital anxiety and depression scale (HADS) scores.ResultsAfter the median of 6 (4–6) weeks of rehabilitation, DHI and VADL scores significantly improved in patients with either peripheral or central vestibular disorders (Wilcoxon signed-rank test, p

ObjectivesA growing body of evidence suggests that age-related hearing loss (HL) is associated with morphological changes of the cerebral cortex, but the results have been drawn from a small amount of data in most studies. The aim of this study is to investigate the correlation between HL and gray matter volume (GMV) in a large number of subjects, strictly controlling for an extensive set of possible biases.MethodsMedical records of 576 subjects who underwent pure tone audiometry, brain magnetic resonance imaging (MRI), and the Korean Mini-Mental State Exam (K-MMSE) were reviewed. Among them, subjects with normal cognitive function and free of central nervous system disorders or coronary artery disease were included. Outliers were excluded after a sample homogeneity check. In the end, 405 subjects were enrolled. Pure tone hearing thresholds were determined at 0.5, 1, 2, and 4 kHz in the better ear. Enrolled subjects were divided into 3 groups according to pure tone average: normal hearing (NH), mild HL (MHL), and moderate-to-severe HL (MSHL) groups. Using voxel-based morphometry, we evaluated GMV changes that may be associated with HL. Sex, age, total intracranial volume, type of MRI scanner, education level, K-MMSE score, smoking status, and presence of hypertension, diabetes mellitus and dyslipidemia were used as covariates.ResultsA statistically significant negative correlation between the hearing thresholds and GMV of the hippocampus was elucidated. Additionally, in group comparisons, the left hippocampal GMV of the MSHL group was significantly smaller than that of the NH and MHL groups.ConclusionBased on the negative correlation between hearing thresholds and hippocampal GMV in cognitively normal old adults, the current study indicates that peripheral deafferentation could be a potential contributing factor to hippocampal atrophy.

IntroductionOnce the underlying pathology has been identified, pulsatile tinnitus (PT) can be treated successfully with surgical or interventional management. However, some patients experience residual or recurrent symptoms following initially successful surgical treatment, and require revision surgery or additional procedures. Here, we report a case series of patients who had undergone revision surgery or interventional treatment, and suggest possible ways of minimizing the need for revision.MethodsBetween January 2014 and March 2023, a total of seven subjects underwent revision surgery or interventional treatment for persistent or recurrent PT after initial surgical treatment. Demographic data, reasons for revision, and changes in symptoms before and after revision were analyzed retrospectively. Temporal bone computed tomographic angiography images were reviewed to identify the causes and reasons for revision.ResultsOf the seven subjects, six underwent sigmoid sinus (SS) resurfacing/reshaping due to ipsilateral diverticulum (Div) or dehiscence (Deh), and one underwent jugular bulb (JB) resurfacing due to a high-riding JB with bony Deh. Of the five subjects who underwent revision SS surgery due to recurrent SS-Div or SS-Deh, three showed marked resolution of PT, while the other two showed partial improvement of the symptoms. One subject who underwent revision JB resurfacing, and another who underwent additional transarterial embolization for a concurrent ipsilateral dural arteriovenous fistula, reported marked improvement of PT.DiscussionThe possibility of recurrence should be taken into account when performing surgical intervention in patients with PT. The likelihood of recurrence can be minimized through a comprehensive evaluation to identify possible multiple etiologies, and through the use of durable materials and appropriate surgical methods.

Tinnitus is defined as the conscious awareness of a sound without an identifiable external sound source, and tinnitus disorder as tinnitus with associated suffering. Chronic tinnitus has been anatomically and phenomenologically separated into three pathways: a lateral “sound” pathway, a medial “suffering” pathway, and a descending noise-canceling pathway. Here, the triple network model is proposed as a unifying framework common to neuropsychiatric disorders. It proposes that abnormal interactions among three cardinal networks—the self-representational default mode network, the behavioral relevance-encoding salience network and the goal-oriented central executive network—underlie brain disorders. Tinnitus commonly leads to negative cognitive, emotional, and autonomic responses, phenomenologically expressed as tinnitus-related suffering, processed by the medial pathway. This anatomically overlaps with the salience network, encoding the behavioral relevance of the sound stimulus. Chronic tinnitus can also become associated with the self-representing default mode network and becomes an intrinsic part of the self-percept. This is likely an energy-saving evolutionary adaptation, by detaching tinnitus from sympathetic energy-consuming activity. Eventually, this can lead to functional disability by interfering with the central executive network. In conclusion, these three pathways can be extended to a triple network model explaining all tinnitus-associated comorbidities. This model paves the way for the development of individualized treatment modalities.

Tinnitus can be defined as the conscious perception of phantom sounds in the absence of corresponding external auditory signals. Tinnitus can develop in the setting of sudden sensorineural hearing loss (SSNHL), but the underlying mechanism is largely unknown. Using electroencephalography, we investigated differences in afferent node capacity between 15 SSNHL patients without tinnitus (NT) and 30 SSNHL patients with tinnitus (T). Where the T group showed increased afferent node capacity in regions constituting a “triple brain network” [default mode network (DMN), central executive network (CEN), and salience network (SN)], the NT group showed increased information flow in regions implicated in temporal auditory processing and noise-canceling pathways. Our results demonstrate that when all components of the triple network are activated due to sudden-onset auditory deprivation, tinnitus ensues. By contrast, auditory processing-associated and tinnitus-suppressing networks are highly activated in the NT group, to overcome the activation of the triple network and effectively suppress the generation of tinnitus.

Abstract Surgical plugging to treat superior semicircular canal dehiscence (SCD) has been proven to impede the effect of the third mobile window, abating cochleovestibular symptoms. Knowledge of superior semicircular canal (SC)-plugging status has been proposed to serve as a guide for adjuvant treatment. Here, we investigated disturbances in the inner ear fluid space following SC plugging using a novel three-dimensional (3D) reconstruction-based method. This approach used a semi-automatic segmentation algorithm and a direct volume rendering method derived from conventional magnetic resonance images. The variable extents of filling defects at the sites of SC plugging and the positional relation of the defect to the ampulla and common crus were identified. The success group exhibited markedly reduced volumes following surgery, whereas the failure group displayed no changes in volume. These results indicate that the success or failure of SC plugging was related to 3D volume changes in the labyrinth fluid signal. Collectively, this study presents individualized SC-plugging statuses using a novel 3D reconstruction-based method and it facilitates future work regarding easy-to-measure 3D volume changes. This current technology also aids in the exploration of pathologic changes in various targets of interest.

A clinical diagnosis of Ménière's disease (MD) is made based on medical history and audiometry findings. The 1995 American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) guidelines requires histopathological confirmation of endolymphatic hydrops (EH) for a diagnosis of “certain” MD. Symptoms such as dizziness and ear fullness are important diagnostic features; however, the descriptions provided by patients are frequently vague and non-specific. A recently developed magnetic resonance imaging (MRI) protocol to document EH is, therefore, useful for the evaluation of inner ear status in patients with MD. In this study, patients with MD were assessed using MRI and the HYDROPS (HYbriD of Reversed image Of Positive endolymph signal and native image of positive perilymph Signal) protocol to investigate the effectiveness of MRI for visualization of the endolymphatic space in the diagnosis of MD by correlating clinical laboratory parameters with the grade of EH. Of the 123 patients with MD recruited in this study, 80 had definite MD, 11 had probable MD, and 32 had possible MD based on the 1995 AAO-HNS guidelines. The EH grade based on HYDROPS MRI was determined independently by two otorhinolaryngologists and compared with several clinical parameters, including the diagnostic scale of MD (1995 AAO-HNS guidelines), pure tone average (PTA), low tone average (LTA), canal paresis (CP) on the caloric test, and disease duration. Cochlear hydrops and vestibular hydrops were detected in 58 and 80% of 80 definite MD ears, in 33 and 58% of 12 probable MD ears, and in 5 and 27% of 37 possible MD ears, respectively. The proportion of higher hydrops grades increased significantly with grade according to the MD diagnostic scale (p < 0.0001). Both PTA and LTA were significantly higher in patients with hydrops grade 2 than hydrops grade 0 in both the cochlea and the vestibule. CP was significantly higher in patients with grade 2 than grade 0 vestibular hydrops. Disease duration was not associated with hydrops grade. Radiological evaluation of MD using the HYDROPS protocol is useful for evaluation of the extent and severity of EH in the diagnosis of MD based on its pathophysiological mechanism.

Abstract Alzheimer’s disease (AD) is the most common cause of age-related dementia. Increasing evidence suggests that neuroinflammation mediated by microglia and astrocytes contributes to disease progression and severity in AD and other neurodegenerative disorders. During AD progression, resident microglia undergo proinflammatory activation, resulting in an increased capacity to convert resting astrocytes to reactive astrocytes. Therefore, microglia are a major therapeutic target for AD and blocking microglia-astrocyte activation could limit neurodegeneration in AD. Here we report that NLY01, an engineered exedin-4, glucagon-like peptide-1 receptor (GLP-1R) agonist, selectively blocks β-amyloid (Aβ)-induced activation of microglia through GLP-1R activation and inhibits the formation of reactive astrocytes as well as preserves neurons in AD models. In two transgenic AD mouse models (5xFAD and 3xTg-AD), repeated subcutaneous administration of NLY01 blocked microglia-mediated reactive astrocyte conversion and preserved neuronal viability, resulting in improved spatial learning and memory. Our study indicates that the GLP-1 pathway plays a critical role in microglia-reactive astrocyte associated neuroinflammation in AD and the effects of NLY01 are primarily mediated through a direct action on Aβ-induced GLP-1R+ microglia, contributing to the inhibition of astrocyte reactivity. These results show that targeting upregulated GLP-1R in microglia is a viable therapy for AD and other neurodegenerative disorders.

Abstract Astrocytes and microglia are brain‐resident glia that can establish harmful inflammatory environments in disease contexts and thereby contribute to the progression of neuronal loss in neurodegenerative disorders. Correcting the diseased properties of glia is therefore an appealing strategy for treating brain diseases. Previous studies have shown that serum/ glucocorticoid related kinase 1 (SGK1) is upregulated in the brains of patients with various neurodegenerative disorders, suggesting its involvement in the pathogenesis of those diseases. In this study, we show that inhibiting glial SGK1 corrects the pro‐inflammatory properties of glia by suppressing the intracellular NFκB‐, NLRP3‐inflammasome‐, and CGAS‐STING‐mediated inflammatory pathways. Furthermore, SGK1 inhibition potentiated glial activity to scavenge glutamate toxicity and prevented glial cell senescence and mitochondrial damage, which have recently been reported as critical pathologic features of and therapeutic targets in Parkinson disease (PD) and Alzheimer disease (AD). Along with those anti‐inflammatory/neurotrophic functions, silencing and pharmacological inhibition of SGK1 protected midbrain dopamine neurons from degeneration and cured pathologic synuclein alpha (SNCA) aggregation and PD‐associated behavioral deficits in multiple in vitro and in vivo PD models. Collectively, these findings suggest that SGK1 inhibition could be a useful strategy for treating PD and other neurodegenerative disorders that share the common pathology of glia‐mediated neuroinflammation.

Objectives Although unilateral hearing loss (UHL) has been proven to be associated with educational and behavioral problems, few studies have investigated psychopathological abnormalities in this population. The aim of this study was to evaluate the psychopathological influence of UHL among Korean 19-year-old males. Methods The authors retrospectively compared the objective personality test profiles of 602 subjects with UHL with those of 23,790 peers with normal hearing. All participants in the current study were 19-year-old males who underwent a physical examination and completed the Korean Military Multiphasic Personality Inventory for conscription at the Military Manpower Administration from February 2015 to December 2016. Results Significantly higher scores were found on neurosis scales in the UHL group than in the normal-hearing group (50.9± 10.8 vs. 44.9±6.0 for anxiety; 51.0±10.5 vs. 44.9±5.2 for depression; 51.1±10.4 vs. 45.1±6.81 for somatization, all P

Summary: Background: The aberrant brain network that gives rise to the phantom sound of tinnitus is believed to determine the effectiveness of tinnitus therapies involving neuromodulation with repetitive transcranial magnetic stimulation (rTMS) and sound therapy utilizing tailor-made notch music training (TMNMT). To test this hypothesis, we determined how effective rTMS or TMNMT were in ameliorating tinnitus in patients with different functional brain networks. Methods: Resting-state functional MRI was used to construct brain functional networks in patients with tinnitus (41 males/45 females, mean age 49.53±11.19 years) and gender-matched healthy controls (22 males/35 females, mean age 46.23±10.23 years) with independent component analysis (ICA). A 2 × 2 analysis of variance with treatment outcomes (Effective group, EG/Ineffective group, IG) and treatment types (rTMS/TMNMT) was used to test the interaction between outcomes and treatment types associated with functional network connections (FNCs). Findings: The optimal neuroimaging indicator for responding to rTMS (AUC 0.804, sensitivity 0.700, specificity 0.913) was FNCs in the salience network-right frontoparietal network (SN-RFPN) while for responding to TMNMT (AUC 0.764, sensitivity 0.864, specificity 0.667) was the combination of FNCs in the auditory network- salience network (AUN-SN) and auditory network-cerebellar network (AUN-CN). Interpretation: Tinnitus patients with higher FNCs in the SN-RFPN is associated with a recommendation for rTMS whereas patients with lower FNCs in the AUN-SN and AUN-CN would suggest TMNMT as the better choice. These results indicate that brain network-based measures aid in the selection of the optimal form of treatment for a patient contributing to advances in precision medicine. Funding: Yuexin Cai is supported by Key R&D Program of Guangdong Province, China (Grant No. 2018B030339001), National Natural Science Foundation of China (82071062), Natural Science Foundation of Guangdong province (2021A1515012038), the Fundamental Research Funds for the Central Universities (20ykpy91), and Sun Yat-Sen Clinical Research Cultivating Program (SYS-Q-201903). Yu-Chen Chen is supported by Medical Science and Technology Development Foundation of Nanjing Department of Health (No. ZKX20037), and Natural Science Foundation of Jiangsu Province (No. BK20211008).

Just as the human brain works in a Bayesian manner to minimize uncertainty regarding external stimuli, a deafferented brain due to hearing loss attempts to obtain or “fill in” the missing auditory information, resulting in auditory phantom percepts (i.e., tinnitus). Among various types of hearing loss, sudden sensorineural hearing loss (SSNHL) has been extensively reported to be associated with tinnitus. However, the reason that tinnitus develops selectively in some patients with SSNHL remains elusive, which led us to hypothesize that patients with SSNHL with tinnitus (SSNHL-T) and those without tinnitus (SSNHL-NT) may exhibit different cortical activity patterns. In the current study, we compared resting-state quantitative electroencephalography findings between 13 SSNHL-T and 13 SSNHL-NT subjects strictly matched for demographic characteristics and hearing thresholds. By performing whole-brain source localization analysis complemented by functional connectivity analysis, we aimed to determine the as-yet-unidentified cortical oscillatory signatures that may reveal potential prerequisites for the perception of tinnitus in patients with SSNHL. Compared with the SSNHL-NT group, the SSNHL-T group showed significantly higher cortical activity in Bayesian inferential network areas such as the frontopolar cortex, orbitofrontal cortex (OFC), and pregenual anterior cingulate cortex (pgACC) for the beta 3 and gamma frequency bands. This suggests that tinnitus develops in a brain with sudden auditory deafferentation only if the Bayesian inferential network updates the missing auditory information and the pgACC-based top-down gatekeeper system is actively involved. Additionally, significantly increased connectivity between the OFC and precuneus for the gamma frequency band was observed in the SSNHL-T group, further suggesting that tinnitus derived from Bayesian inference may be linked to the default mode network so that tinnitus is regarded as normal. Taken together, our preliminary results suggest a possible mechanism for the selective development of tinnitus in patients with SSNHL. Also, these areas could serve as the potential targets of neuromodulatory approaches to preventing the development or prolonged perception of tinnitus in subjects with SSNHL.

Thalamocortical dysrhythmia has been proposed to occur in a number of neurological and psychiatric disorders. Here, the authors use a data-driven approach to demonstrate thalamocortical dysrhythmia occurs in individuals with Parkinson’s disease, neuropathic pain, tinnitus, and depression.

Abstract Although neurovascular compression of the cochlear nerve (NVC-C) presenting as typewriter tinnitus is a discrete disease category, verified diagnostic criteria are lacking. We sought to refine the diagnostic criteria for NVC-C by reference to a relatively large case series. The medical records of 22 NVC-C patients were retrospectively reviewed. Psychoacoustic characteristics, the results of diagnostic work-up (including audiovestibular neurophysiological tests and radiological evaluations), and the initial treatment response to carbamazepine were investigated. All subjects described their tinnitus as a typical “typewriter” or “staccato” sound. Of the 22 subjects, 11 (50%) had histories of vertiginous spells, but none had ipsilesional hearing loss. Vestibular function tests in 11 subjects tested revealed only 2 (18.2%) isolated cervical vestibular evoked myogenic potential abnormalities. Radiological comparisons of the symptomatic and asymptomatic sides, regarding the type of the vascular loop and neurovascular contact, revealed no significant differences. However, all 22 subjects exhibited immediate and marked responses to short-term carbamazepine treatment. Meticulous history-taking in terms of the psychoacoustic characteristics and the response to initial carbamazepine, are more reliable diagnostic clues than are radiological or neurophysiological data in NVC-C subjects. Therefore, the typical psychoacoustic characteristics and the response to initial carbamazepine should be included in the diagnostic criteria.

Objectives: The aim of this study was to delineate the clinical and laboratory features suggestive of intralabyrinthine schwannoma (ILS).Methods: We compared the clinical features of 16 patients with ILS, who had been diagnosed at the Seoul National University Bundang Hospital from 2003 to 2018, with those of 18 patients with symptomatic unilateral intracanalicular schwannoma and randomly selected 20 patients with definite or probable unilateral Meniere's disease (MD).Results: Patients with ILS presented with either recurrent spontaneous dizziness/vertigo combined with auditory symptoms (n = 8), isolated auditory symptoms without dizziness/vertigo (n = 7), or recurrent spontaneous dizziness/vertigo without auditory symptoms (n = 1). Most patients reported no improvement (n = 11) or worsening (n = 1) of the symptoms despite medical treatments including intratympanic (n = 5) or intravenous steroids (n = 2). Conventional brain MRIs failed to detect ILS in about a half of the patients (7/16, 44%). However, ILS showed a filling defect on 3-dimensional (3D) heavily T2-weighted MRIs (n = 12), and nodular enhancement on 3D contrast-enhanced T1 (n = 15) or FLAIR MRIs (n = 13) targeted for the inner ear. Compared to MD or intracanalicular schwannoma, ILS showed mostly abnormal head-impulse tests (HITs, p = 0.001). In contrast, the incidence of canal paresis did not differ among the groups (p = 0.513).Conclusion: ILS may mimic MD by presenting recurrent dizziness/vertigo and auditory symptoms. ILS should be suspected in patients with recurrent audiovestibulopathy especially when (1) the duration of the dizziness is not typical for MD, (2) the patients do not respond to medical treatments, or (3) HITs are abnormal.

Objectives To investigate longitudinal changes in behavior and quality-of-life (QoL) in children with sleep disordered breathing (SDB) after adenotonsillectomy (AT). Methods This study prospectively enrolled 148 children who underwent AT for SDB. Caregivers filled out Korean attention deficit hyperactivity disorder (ADHD) rating scale (K-ARS) and Korean version of the obstructive sleep apnea-18 (KOSA-18) at preoperative 1 day, postoperative 1 month, and postoperative 6 months. Longitudinal changes in K-ARS and KOSA-18 were evaluated and compared among subgroups. Results Both K-ARS and KOSA-18 scores improved immediately at postoperative 1 month and were maintained at postoperative 6 months. The mean preoperative K-ARS scores of the non-ADHD, ADHD-trait, and overt-ADHD groups showed uniformly immediate and sustained improvements. Also, the mean preoperative KOSA-18 scores of the small, moderate, and large impact groups were significantly improved both at postoperative 1 month and 6 months. The changes in behavior and QoL showed no significant differences with regard to the aforementioned factors. Conclusion After AT, we may expect immediate and sustained improvements in behavior and QoL in children with SDB regardless of preoperative symptom severity. Moreover, by performing AT, improvements in behavior and QoL are expected regardless of sex, age, allergic trait, or concurrent coblation-assisted turbinoplasty. These findings may help our colleague physicians counselling pediatric SDB patients and their caregivers.

Routine application of next-generation sequencing in clinical settings is often limited by time- and cost-prohibitive complex filtering steps. Despite the previously introduced genotyping kit that allows screening of the 11 major recurring variants of sensorineural hearing loss (SNHL) genes in the Korean population, the demand for phenotype- and variant-specific screening kits still remains. Herein, we developed a new real-time PCR-based kit (U-TOP™ HL Genotyping Kit Ver2), comprising six variants from two auditory neuropathy spectrum disorder (ANSD) genes (OTOF and ATP1A3) and five variants from three SNHL genes (MPZL2, COCH, and TMC1), with a distinct auditory phenotype, making this the first genotyping kit dedicated to ANSD. The concordance rate with Sanger sequencing, sensitivity, and specificity of this genotyping kit were all 100%, suggesting reliability. The kit not only allows timely and cost-effective identification of recurring OTOF variants, but it also allows timely detection of cochlear nerve deficiency for those without OTOF variants. Herein, we provide a clinical guideline for an efficient, rapid, and cost-effective etiologic diagnosis of prelingual ANSD. Our study provides a good example of continuing to update new key genetic variants, which will continuously be revealed through NGS, as targets for the newly developed genotyping kit.

Abstract Use of the physiological mechanisms promoting midbrain DA (mDA) neuron survival seems an appropriate option for developing treatments for Parkinson's disease (PD). mDA neurons are specifically marked by expression of the transcription factors Nurr1 and Foxa2. We show herein that Nurr1 and Foxa2 interact to protect mDA neurons against various toxic insults, but their expression is lost during aging and degenerative processes. In addition to their proposed cell‐autonomous actions in mDA neurons, forced expression of these factors in neighboring glia synergistically protects degenerating mDA neurons in a paracrine mode. As a consequence of these bimodal actions, adeno‐associated virus (AAV)‐mediated gene delivery of Nurr1 and Foxa2 in a PD mouse model markedly protected mDA neurons and motor behaviors associated with nigrostriatal DA neurotransmission. The effects of the combined gene delivery were dramatic, highly reproducible, and sustained for at least 1 year, suggesting that expression of these factors is a promising approach in PD therapy.

Multiple wavelength light sources in the medical spectral window region are useful for various medical sensing applications in tissue by distinguishing the absorption and scattering coefficients optically. We propose a simultaneous second harmonic generation of multiple wavelength fiber laser output using parallel channels of periodically-poled lithium niobate (PPLN) waveguides. High intensity dual wavelength lasing output is experimentally realized with two tunable fiber Bragg gratings of 1,547.20 nm and 1,554.48 nm for the efficient conversion to the half wavelengths, 773.60 nm and 777.24 nm, by using two parallel PPLN channels. Compared with a conventional dual second harmonic generation (SHG) configuration based on two different input wavelengths from each independent light source, this method has a relatively higher efficiency to align the input light beam into the adjacent parallel PPLN channels simultaneously. The use of fiber lasers offers several advantages since they are relatively inexpensive, provide high power in excess of tens of watts, are widely tunable, and can produce pulses from milliseconds to femtoseconds.