Variability in Cochlear Implantation Outcomes in a Large German Cohort With a Genetic Etiology of Hearing Loss.

OBJECTIVES: The variability in outcomes of cochlear implantation is largely unexplained, and clinical factors are not sufficient for predicting performance. Genetic factors have been suggested to impact outcomes, but the clinical and genetic heterogeneity of hereditary hearing loss makes it difficult to determine and interpret postoperative performance. It is hypothesized that genetic mutations that affect the neuronal components of the cochlea and auditory pathway, targeted by the cochlear implant (CI), may lead to poor performance. A large cohort of CI recipients was studied to verify this hypothesis. DESIGN: This study included a large German cohort of CI recipients (n = 123 implanted ears; n = 76 probands) with a definitive genetic etiology of hearing loss according to the American College of Medical Genetics (ACMG)/Association for Molecular Pathology (AMP) guidelines and documented postoperative audiological outcomes. All patients underwent preoperative clinical and audiological examinations. Postoperative CI outcome measures were based on at least 1 year of postoperative audiological follow-up for patients with postlingual hearing loss onset (>6 years) and 5 years for children with congenital or pre/perilingual hearing loss onset (≤6 years). Genetic analysis was performed based on three different methods that included single-gene screening, custom-designed hearing loss gene panel sequencing, targeting known syndromic and nonsyndromic hearing loss genes, and whole-genome sequencing. RESULTS: The genetic diagnosis of the 76 probands in the genetic cohort involved 35 genes and 61 different clinically relevant (pathogenic, likely pathogenic) variants. With regard to implanted ears (n = 123), the six most frequently affected genes affecting nearly one-half of implanted ears were GJB2 (21%; n = 26), TMPRSS3 (7%; n = 9), MYO15A (7%; n = 8), SLC26A4 (5%; n = 6), and LOXHD1 and USH2A (each 4%; n = 5). CI recipients with pathogenic variants that influence the sensory nonneural structures performed at or above the median level of speech performance of all ears at 70% [monosyllable word recognition score in quiet at 65 decibels sound pressure level (SPL)]. When gene expression categories were compared to demographic and clinical categories (total number of compared categories: n = 30), mutations in genes expressed in the spiral ganglion emerged as a significant factor more negatively affecting cochlear implantation outcomes than all clinical parameters. An ANOVA of a reduced set of genetic and clinical categories (n = 10) identified five detrimental factors leading to poorer performance with highly significant effects ( p < 0.001), accounting for a total of 11.8% of the observed variance. The single strongest category was neural gene expression accounting for 3.1% of the variance. CONCLUSIONS: The analysis of the relationship between the molecular genetic diagnoses of a hereditary etiology of hearing loss and cochlear implantation outcomes in a large German cohort of CI recipients revealed significant variabilities. Poor performance was observed with genetic mutations that affected the neural components of the cochlea, supporting the "spiral ganglion hypothesis."

Diagnostic Yield of Targeted Hearing Loss Gene Panel Sequencing in a Large German Cohort With a Balanced Age Distribution from a Single Diagnostic Center: An Eight-year Study.

OBJECTIVES: Hereditary hearing loss exhibits high degrees of genetic and clinical heterogeneity. To elucidate the population-specific and age-related genetic and clinical spectra of hereditary hearing loss, we investigated the sequencing data of causally associated hearing loss genes in a large cohort of hearing-impaired probands with a balanced age distribution from a single center in Southwest Germany. DESIGN: Genetic testing was applied to 305 hearing-impaired probands/families with a suspected genetic hearing loss etiology and a balanced age distribution over a period of 8 years (2011-2018). These individuals were representative of the regional population according to age and sex distributions. The genetic testing workflow consisted of single-gene screening (n = 21) and custom-designed hearing loss gene panel sequencing (n = 284) targeting known nonsyndromic and syndromic hearing loss genes in a diagnostic setup. Retrospective reanalysis of sequencing data was conducted by applying the current American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. RESULTS: A genetic diagnosis was established for 75 (25%) of the probands that involved 75 causal variants in 35 genes, including 16 novel causal variants and 9 medically significant variant reclassifications. Nearly half of the solved cases (47%; n = 35) were related to variants in the five most frequently affected genes: GJB2 (25%), MYO15A, WFS1, SLC26A4, and COL11A1 (all 5%). Nearly one-quarter of the cases (23%; n = 17) were associated with variants in seven additional genes (TMPRSS3, COL4A3, LOXHD1, EDNRB, MYO6, TECTA, and USH2A). The remaining one-third of single cases (33%; n = 25) were linked to variants in 25 distinct genes. Diagnostic rates and gene distribution were highly dependent on phenotypic characteristics. A positive family history of autosomal-recessive inheritance in combination with early onset and higher grades of hearing loss significantly increased the solve rate up to 60%, while late onset and lower grades of hearing loss yielded significantly fewer diagnoses. Regarding genetic diagnoses, autosomal-dominant genes accounted for 37%, autosomal-recessive genes for 60%, and X-linked genes for 3% of the solved cases. Syndromic/nonsyndromic hearing loss mimic genes were affected in 27% of the genetic diagnoses. CONCLUSIONS: The genetic epidemiology of the largest German cohort subjected to comprehensive targeted sequencing for hereditary hearing loss to date revealed broad causal gene and variant spectra in this population. Targeted hearing loss gene panel analysis proved to be an effective tool for ensuring an appropriate diagnostic yield in a routine clinical setting including the identification of novel variants and medically significant reclassifications. Solve rates were highly sensitive to phenotypic characteristics. The unique population-adapted and balanced age distribution of the cohort favoring late hearing loss onset uncovered a markedly large contribution of autosomal-dominant genes to the diagnoses which may be a representative for other age balanced cohorts in other populations.

Coupling of an active middle-ear implant to the long process of the incus using an elastic clip attachment.

The active middle-ear implant Vibrant Soundbridge© (VSB) is used to treat mild-to-severe sensorineural hearing losses. The standard surgical approach for incus vibroplasty is a mastoidectomy and a posterior tympanotomy, crimping the Floating Mass Transducer (FMT) to the long process of the incus (LPI) (standard crimped application). However, tight crimping increases the risk of necrosis of the LPI, resulting in reduction of energy transfer and loss of amplification. The aim of this study was to develop a new coupling device for the LPI, that does not require crimping, and to test its vibrational transfer properties in temporal-bone preparations. An extended antrotomy and a posterior tympanotomy were performed in ten fresh human temporal bones. As a control for normal middle-ear function, the tympanic membrane was stimulated acoustically and the vibration of the stapes footplate was measured by laser Doppler vibrometry (LDV). FMT-induced vibration responses of the stapes were then measured for the standard crimped application at the LPI and for the newly designed elastic long process coupler (LP coupler). For the LP coupler, velocity-amplitude responses in temporal-bone preparations showed increased mean amplitudes at around 1 kHz (∼10 dB) and a reduction between 1.8 and 6 kHz (13 dB on average for 2 ≤ f ≤ 5 kHz). In conclusion, attachment of the FMT to the LPI with the LP coupler leads to generally good mechanical and functional coupling in temporal-bone preparations with a notable disadvantage between 1.8 and 6 kHz. Due to its elastic clip attachment it is expected that the LP coupler will reduce the risk of necrosis of the incus long process, which has to been shown in further studies. Clinical results of the LP coupler are pending.

Standardized Active Middle-Ear Implant Coupling to the Short Incus Process.

INTRODUCTION: Active middle-ear implants with floating-mass transducer (FMT) technology are used to treat mild-to-severe sensorineural hearing losses. The standard surgical approach for incus vibroplasty is a mastoidectomy and a posterior tympanotomy, crimping the FMT to the long incus process. An alternative fixation side with less surgical trauma might be the short incus process and incus body.The aim of this study was to develop and test a short incus process coupling device for its functional properties in temporal bone preparations and clinical practice. MATERIALS AND METHODS: An extended antrotomy and a posterior tympanotomy were performed in 10 fresh human temporal bones. As a control for normal middle-ear function, the tympanic membrane was stimulated acoustically, and the vibration of the stapes footplate was measured using laser Doppler vibrometry. FMT-induced vibration responses of the stapes were then measured for standard attachment at the long process and for 2 types of couplers designed for attachment at the short process of the incus (SP1 and SP2 coupler). Additionally, the functional outcome in 2 patients provided with an SP2 coupler was assessed postoperatively at 2 weeks, 3 months, and then 11 months, using pure-tone audiometry, auditory thresholds for frequency-modulated (warble) tones, vibroplasty thresholds, and speech audiometry in quiet and noise. RESULTS: For the SP2 coupler, velocity-amplitude responses in temporal-bone preparations showed generally similar mean amplitudes as compared with the standard coupling of the FMT to the long process but with clearly increased mean amplitudes between 0.7 and 1.5 kHz and with reduced interindividual variation between 0.5 and 3 kHz. The clinical data of 2 patients with mild-to-severe sensory hearing loss showed good vibroplasty thresholds and convincing results for speech audiometry in quiet (Freiburger monosyllables at 65 dB SPL, 23 ± 31% unaided versus 83 ± 4% aided) and noise (Hochmair-Schulz-Moser-test at 65 dB SPL at 10 dB SNR, 32 ± 45% unaided and 42 ± 29% aided). CONCLUSION: The attachment of the FMT to the short incus process with the SP2 coupler leads to good mechanical and functional coupling in an experimental setup and clinical practice.

Reinforced active middle ear implant fixation in incus vibroplasty.

OBJECTIVES: The active middle ear implant Vibrant Soundbridge® was originally designed to treat mild-to-severe sensorineural hearing losses. The floating mass transducer (FMT) is crimped onto the long incus process. The procedure is termed incus vibroplasty to distinguish from other attachment sites or stimulus modi for treating conductive and mixed hearing losses. Rare but possible complications are difficult incus anatomy, necrosis of the long incus process, secondary detachment, and loosening of the FMT with concomitant amplification loss. The aim of this study was to functionally evaluate reinforcement of the standard attachment of the FMT to the long incus process. The head of a Soft CliP® stapes prosthesis was used for reinforcement. Functional evaluation was performed in temporal-bone preparations and in clinical practice. DESIGN: A subtotal mastoidectomy and a posterior tympanotomy were performed in ten fresh human temporal bones. As a control for normal middle-ear function, the tympanic membrane was stimulated acoustically and the vibration of the stapes footplate and the round-window (RW) membrane, respectively, were measured by laser Doppler vibrometer (LDV). FMT-induced vibration responses of the stapes and RW were then measured for standard attachment and attachment reinforced with the head of a Soft CliP® stapes prosthesis. Additionally, the outcome in two groups of patients with incus vibroplasty using standard and the reinforced FMT attachment were compared. Eleven patients were treated by standard coupling; nine patients obtained reinforcement with the head of the Soft CliP® stapes prosthesis. Three to six months postoperatively, auditory thresholds for frequency-modulated (warble) tones and vibroplasty thresholds for pure tones were measured. RESULTS: In temporal bone, laser Doppler vibrometer measurements showed significantly enhanced vibration amplitudes of the stapes footplate and the RW membrane for the reinforced attachment compared with those for the standard attachment (on average, 5-10 dB at frequencies below 1 kHz and above 4 kHz). Interindividual amplitude variations were also smaller for reinforced attachment (on average, the standard deviation was 4-7 dB smaller). The clinical data showed lower vibroplasty thresholds for reinforced attachment compared with standard attachment, which amounted to, on average, 16 dB at 500 Hz and 12 dB at 4 kHz. CONCLUSION: Auxiliary fixation of the FMT by reinforcing the attachment to the long incus process, in these experiments with the head of a Soft CliP stapes prosthesis, leads to enhanced mechanical and functional coupling, evidenced by lower vibroplasty thresholds and increased bandwidth together with reduced variability of the vibrational frequency responses of the stapes footplate and RW membrane.

Developmental stage-specific regulation of the circadian clock by temperature in zebrafish.

The circadian clock enables animals to adapt their physiology and behaviour in anticipation of the day-night cycle. Light and temperature represent two key environmental timing cues (zeitgebers) able to reset this mechanism and so maintain its synchronization with the environmental cycle. One key challenge is to unravel how the regulation of the clock by zeitgebers matures during early development. The zebrafish is an ideal model for studying circadian clock ontogeny since the process of development occurs ex utero in an optically transparent chorion and many tools are available for genetic analysis. However, the role played by temperature in regulating the clock during zebrafish development is poorly understood. Here, we have established a clock-regulated luciferase reporter transgenic zebrafish line (Tg (-3.1) per1b::luc) to study the effects of temperature on clock entrainment. We reveal that under complete darkness, from an early developmental stage onwards (48 to 72 hpf), exposure to temperature cycles is a prerequisite for the establishment of self-sustaining rhythms of zfper1b, zfaanat2, and zfirbp expression and also for circadian cell cycle rhythms. Furthermore, we show that following the 5-9 somite stage, the expression of zfper1b is regulated by acute temperature shifts.

Assessment of the noise-protective action of the olivocochlear efferents in humans.

It has been demonstrated in different mammals that the medial olivocochlear efferents (MOC) exert a noise-protective effect on the cochlea. In humans such an effect has not unambiguously been shown as of yet. The objective of this study was to assess the relationship between MOC activity and susceptibility of the cochlea to noise-induced hearing loss in humans. In 40 normally hearing human subjects, we measured the following: (1) magnitude of temporary threshold shift (TTS) after exposure to 60 min broadband noise of 94 dB SPL and (2) contralateral suppression (CS) of distortion product otoacoustic emissions (which reflects MOC activity) using two different measurement paradigms. CS was measured in duplicate on 2 measurement days. The relationship between TTS and CS was assessed. Individual TTS in the most affected frequencies (4 > 3 > 8 kHz) ranged from 9 to 28 dB HL, with an average maximum TTS of 18.4 dB HL. The amount of CS ranged between 0.3 and 3 dB. The repeatability of CS, evaluated by Cronbach's α value, ranged from 0.76 (acceptable repeatability) to 0.86 (good repeatability). One of the two different measurement paradigms showed a statistically significant inverse correlation between CS magnitude and amount of TTS, which was hypothesized. This is the first study on the relationship between TTS and CS in humans employing TTS induced under controlled laboratory conditions and two different MOC paradigms. The findings are compatible with the hypothesis that MOC activity is noise protective in humans. Future perspectives include modified CS paradigms, longitudinal cohort studies or efforts to also monitor lateral efferent effects in humans.

Concept and evaluation of an endaurally insertable middle-ear implant.

A concept for a partially implantable hearing device, for which the power supply and signal transmission are provided by an optical transmission path, is evaluated. The actuator is designed to fit into the round-window niche and to couple directly to the round-window membrane. Implantable hearing aids can be a suitable solution in the case of severe hearing loss, where conventional hearing aids often fail. However, the surgical effort for an implantation is comparatively high. Therefore, the objective of our work was to provide a hearing system which combines reliable coupling to the auditory system with an easy implantation technique. The actuator was designed as a piezoelectric thin-film cantilever. The optical transmission path was realised using an infrared light-emitting diode combined with an active receiver circuit. For a voltage of 1V, the unloaded actuator presents displacement amplitudes of 1µm up to a stimulus frequency of 25kHz and forces up to 0.2mN. Proportionally larger forces can be achieved by stacking single actuators. The overall transmission loss from the electrical input of the light-emitting diode driver to the mechanical output of the unloaded actuator was less than 25dB at 1kHz and maximum output.

Conditions for highly efficient and reproducible round-window stimulation in humans.

Round-window stimulation is a new clinical approach for the application of active middle-ear implants. To investigate factors influencing the efficiency of round-window stimulation, experiments in 6 human temporal bones were performed with different actuator geometries and coupling conditions. The experiments show that the amplitude ratio between stapes and round-window actuator vibration is most efficient when using a 1.0-mm diameter rod with a 30° inclined tip geometry and an attached silicone pad. In this case, the amplitude ratio is 0.34 for frequencies up to 1.5 kHz and 0.27 for frequencies up to 20 kHz, with a standard deviation of only 4-6 dB at most frequencies. The analysis of data presented here and in a companion paper suggests that control of proper round-window membrane pretension as well as the inclined tip geometry are the major requirements for maximal performance.

Measurement of medial olivocochlear efferent activity in humans: comparison of different distortion product otoacoustic emission-based paradigms.

OBJECTIVE: To assess the suitability of contralateral suppression (CS) of distortion product otoacoustic emissions (DPOAEs) for measurement of activity of the medial olivocochlear (MOC) efferents. BACKGROUND: The MOC efferent system has been shown to be involved in sound discrimination, selective attention to tones, sound localization, and protection of the cochlea against noise. A great variety of paradigms for measurement of MOC activity by CS of OAE (MOC reflex [MOCR]), has been described. An issue of this approach is the dependence of the CS values on stimulus parameters, especially when DPOAE are used. METHODS: Four different measurement paradigms, which used different combinations of stimulus frequencies and primary tone levels, were applied in 16 human subjects. RESULTS: Mean absolute values of CS were in the range of 1.2 to 2.6 dB. The use of different stimulus parameters produced not only MOCR values of different size-which was expected-but, in many cases, also different relative classifications of the subjects according to their MOCR strength. CONCLUSION: The suppression effects on DPOAE demonstrated in this study reflect MOC activity. However, the new conclusion from our data is that CS of DPOAE measurements, as they were used in this study, may not allow for a consistent quantitative classification of human subjects according to their MOCR strength. This finding concerns interpretation of previous studies using CS of DPOAE and analogous future studies. One future approach may lie in the separation of the DPOAE components to distinguish interference phenomena, which complicate interpretation of CS values.