Neural Adaptation at Stimulus Onset and Speed of Neural Processing as Critical Contributors to Speech Comprehension Independent of Hearing Threshold or Age.

Background: It is assumed that speech comprehension deficits in background noise are caused by age-related or acquired hearing loss. Methods: We examined young, middle-aged, and older individuals with and without hearing threshold loss using pure-tone (PT) audiometry, short-pulsed distortion-product otoacoustic emissions (pDPOAEs), auditory brainstem responses (ABRs), auditory steady-state responses (ASSRs), speech comprehension (OLSA), and syllable discrimination in quiet and noise. Results: A noticeable decline of hearing sensitivity in extended high-frequency regions and its influence on low-frequency-induced ABRs was striking. When testing for differences in OLSA thresholds normalized for PT thresholds (PTTs), marked differences in speech comprehension ability exist not only in noise, but also in quiet, and they exist throughout the whole age range investigated. Listeners with poor speech comprehension in quiet exhibited a relatively lower pDPOAE and, thus, cochlear amplifier performance independent of PTT, smaller and delayed ABRs, and lower performance in vowel-phoneme discrimination below phase-locking limits (/o/-/u/). When OLSA was tested in noise, listeners with poor speech comprehension independent of PTT had larger pDPOAEs and, thus, cochlear amplifier performance, larger ASSR amplitudes, and higher uncomfortable loudness levels, all linked with lower performance of vowel-phoneme discrimination above the phase-locking limit (/i/-/y/). Conslusions: This study indicates that listening in noise in humans has a sizable disadvantage in envelope coding when basilar-membrane compression is compromised. Clearly, and in contrast to previous assumptions, both good and poor speech comprehension can exist independently of differences in PTTs and age, a phenomenon that urgently requires improved techniques to diagnose sound processing at stimulus onset in the clinical routine.

A phase I/IIa safety and efficacy trial of intratympanic gamma-secretase inhibitor as a regenerative drug treatment for sensorineural hearing loss.

Inhibition of Notch signalling with a gamma-secretase inhibitor (GSI) induces mammalian hair cell regeneration and partial hearing restoration. In this proof-of-concept Phase I/IIa multiple-ascending dose open-label trial (ISRCTN59733689), adults with mild-moderate sensorineural hearing loss received 3 intratympanic injections of GSI LY3056480, in 1 ear over 2 weeks. Phase I primary outcome was safety and tolerability. Phase lla primary outcome was change from baseline to 12 weeks in average pure-tone air conduction threshold across 2,4,8 kHz. Secondary outcomes included this outcome at 6 weeks and change from baseline to 6 and 12 weeks in pure-tone thresholds at individual frequencies, speech reception thresholds (SRTs), Distortion Product Otoacoustic Emissions (DPOAE) amplitudes, Signal to Noise Ratios (SNRs) and distribution of categories normal, present-abnormal, absent and Hearing Handicap Inventory for Adults/Elderly (HHIA/E). In Phase I (N = 15, 1 site) there were no severe nor serious adverse events. In Phase IIa (N = 44, 3 sites) the average pure-tone threshold across 2,4,8 kHz did not change from baseline to 6 and 12 weeks (estimated change -0.87 dB; 95% CI -2.37 to 0.63; P = 0.252 and -0.46 dB; 95% CI -1.94 to 1.03; P = 0.545, respectively), nor did the means of secondary measures. DPOAE amplitudes, SNRs and distribution of categories did not change from baseline to 6 and 12 weeks, nor did SRTs and HHIA/E scores. Intratympanic delivery of LY3056480 is safe and well-tolerated; the trial's primary endpoint was not met.

Differential cortical activation patterns: pioneering sub-classification of tinnitus with and without hyperacusis by combining audiometry, gamma oscillations, and hemodynamics.

The ongoing controversies about the neural basis of tinnitus, whether linked with central neural gain or not, may hamper efforts to develop therapies. We asked to what extent measurable audiometric characteristics of tinnitus without (T) or with co-occurrence of hyperacusis (TH) are distinguishable on the level of cortical responses. To accomplish this, electroencephalography (EEG) and concurrent functional near-infrared spectroscopy (fNIRS) were measured while patients performed an attentionally demanding auditory discrimination task using stimuli within the individual tinnitus frequency (fTin) and a reference frequency (fRef). Resting-state-fMRI-based functional connectivity (rs-fMRI-bfc) in ascending auditory nuclei (AAN), the primary auditory cortex (AC-I), and four other regions relevant for directing attention or regulating distress in temporal, parietal, and prefrontal cortex was compiled and compared to EEG and concurrent fNIRS activity in the same brain areas. We observed no group differences in pure-tone audiometry (PTA) between 10 and 16 kHz. However, the PTA threshold around the tinnitus pitch was positively correlated with the self-rated tinnitus loudness and also correlated with distress in T-groups, while TH experienced their tinnitus loudness at minimal loudness levels already with maximal suffering scores. The T-group exhibited prolonged auditory brain stem (ABR) wave I latency and reduced ABR wave V amplitudes (indicating reduced neural synchrony in the brainstem), which were associated with lower rs-fMRI-bfc between AAN and the AC-I, as observed in previous studies. In T-subjects, these features were linked with elevated spontaneous and reduced evoked gamma oscillations and with reduced deoxygenated hemoglobin (deoxy-Hb) concentrations in response to stimulation with lower frequencies in temporal cortex (Brodmann area (BA) 41, 42, 22), implying less synchronous auditory responses during active auditory discrimination of reference frequencies. In contrast, in the TH-group gamma oscillations and hemodynamic responses in temporoparietal regions were reversed during active discrimination of tinnitus frequencies. Our findings suggest that T and TH differ in auditory discrimination and memory-dependent directed attention during active discrimination at either tinnitus or reference frequencies, offering a test paradigm that may allow for more precise sub-classification of tinnitus and future improved treatment approaches.

Neural substrates of tinnitus severity.

Subjective chronic tinnitus is a prevalent auditory perception characterized by an absence of a corresponding acoustic source. It is often accompanied by hearing deficits and may lead to various psychological problems including sleep disorder, depression and anxiety. To investigate the differential neuronal profile of patients with severe and less severe chronic tinnitus, 34 tinnitus patients were distributed in two groups and their EEG resting state activity was compared. Using standardized Low Resolution Electromagnetic Tomography (sLORETA) a significant and substantial frontal increase in theta wave activity was found in the group with severe tinnitus (p = .013). The correlated severity of depression and anxiety had no influence on the electrophysiological metric. These results support a tinnitus-related global network change in which prefrontal areas are part of a network which exerts a top-down influence on the auditory cortices. The demonstrated slowing of oscillations in the responsible network may constitute a neuronal marker for the prefrontal brain network lacking the capacity to inhibit overexcitation. The magnitude of this influence is linked to the subjective strength of the tinnitus distress.

The ototoxic effect of locally applied kanamycin and furosemide in guinea pigs.

BACKGROUND: Hearing impairment is a growing social and economic issue. New technical or biological approaches aiming hearing rehabilitation or regeneration require animal testing. Therefore, a reproducible and safe model for hearing-impaired animals is essential. NEW METHOD: Intratympanic injection of kanamycin and furosemide was administered for BFA bunt pigmented guinea pigs for either 1 or 2 h. Hearing loss was regularly measured with compound action potential response to click and tone burst stimuli for up to 26 weeks. Hair cell loss and the density of spiral ganglion neurons were histologically analyzed. RESULTS: One week after the exposure, complete hearing loss was observed in 34 ears from the 36 ears treated for 2 h and remained stable during the follow-up. Histology revealed near complete hair cell loss and secondary degeneration of spiral ganglion neurons. COMPARISON WITH EXISTING METHODS: Animal deafening is usually achieved by systemic application of aminoglycoside antibiotics or chemotherapy drugs, although side effects such as nephrotoxicity may occur which can be avoided by local application. With our procedure, unilateral hearing loss model can also be established. CONCLUSIONS: The single intratympanic application of a solution of 200 mg/ml kanamycin and 50 mg/ml furosemide is a stable and reliable deafening method.

Psychophysiological treatment of chronic tinnitus: A review.

Subjective chronic tinnitus consists of a more or less continuous perception of sound in the absence of a corresponding acoustic source, which can lead to various psychological problems like depression, anxiety, attentional deficits and sleep disturbances. The prevalence is 10%-15% of the general population. Various therapy and management options have been proposed, but outcomes vary, and no generally accepted cure exists. In this review, the coherence of the most frequently used aetiological models shall be evaluated, and the efficacy of several treatment options will be discussed. With respect to tinnitus treatments, we focus on controlled studies and meta-analyses. Although there are some therapies that outweigh placebo effects such as cognitive behavioural therapy, neurofeedback or neuromodulation techniques, they mainly target secondary symptoms and not the tinnitus tone itself. Furthermore, positive treatment effects only seem to last for a limited period of time. We conclude that long-lasting combination therapies such as neurofeedback of auditory cortex inhibitory EEG signatures, cognitive therapy and sound-tactile stimulation may provide more efficient outcomes if they target the intensity of the tinnitus tone itself and not only secondary psychological symptoms.

International Survey of Operative Practices for Otologists and Neurotologists During the COVID-19 Crisis.

OBJECTIVE: To investigate the influence of the COVID-19 pandemic on operative practices of otology and neurotology providers internationally. STUDY DESIGN: Cross-sectional survey. METHODS: A 78-question survey was distributed to otologists and neurotologists between May 12, 2020 and June 8, 2020 to assess the impact of the pandemic on surgical practices. Sections within the survey delineated time periods: prior to the crisis, onset of the crisis, during the crisis, postcrisis transition. RESULTS: Of 396 survey respondents, 284 participants from 38 countries met inclusion criteria.Respondents were 16.9% female and 82.4% male, with a most common age range of 40 to 49 years (36.3%). 69.8% of participants had been in practice for over 10 years and most respondents worked in an academic medical center (79.2%). The average operative weekly caseload was 5.3 (SD 3.9) per surgeon prior to the crisis, 0.7 (SD 1.2) during the COVID-19 crisis, and 3.5 (SD 3.3) for those who had begun a postcrisis transition at the time of survey administration (p < 0.001). 71.5% of providers did not perform an elective otologic or neurotologic operative procedure during the initial crisis period. 49.8% reported modifying their surgical technique due to the COVID-19 pandemic. Use of powered air-purifying respirators and filtering facepiece 2 or 3 (FFP2/FFP3) respirators were in minimal supply for 66.9% and 62.3% of respondents, respectively. CONCLUSION: The COVID-19 pandemic impacted the otology and neurotology community globally, resulting in significant changes in operative volume and case selection. Modification of surgical technique and shortages of personal protective equipment were frequently reported.

Co-occurrence of Hyperacusis Accelerates With Tinnitus Burden Over Time and Requires Medical Care.

Although tinnitus represents a major global burden, no causal therapy has yet been established. Ongoing controversies about the neuronal pathophysiology of tinnitus hamper efforts in developing advanced therapies. Hypothesizing that the unnoticed co-occurrence of hyperacusis and differences in the duration of tinnitus may possibly differentially influence the neural correlate of tinnitus, we analyzed 33 tinnitus patients without (T-group) and 20 tinnitus patients with hyperacusis (TH-group). We found crucial differences between the T-group and the TH-group in the increase of annoyance, complaints, tinnitus loudness, and central neural gain as a function of tinnitus duration. Hearing thresholds did not differ between T-group and TH-group. In the TH-group, the tinnitus complaints (total tinnitus score) were significantly greater from early on and the tinnitus intensity distinctly increased over time from ca. 12 to 17 dB when tinnitus persisted more than 5 years, while annoyance responses to normal sound remained nearly constant. In contrast, in the T-group tinnitus complaints remained constant, although the tinnitus intensity declined over time from ca. 27 down to 15 dB beyond 5 years of tinnitus persistence. This was explained through a gradually increased annoyance to normal sound over time, shown by a hyperacusis questionnaire. Parallel a shift from a mainly unilateral (only 17% bilateral) to a completely bilateral (100%) tinnitus percept occurred in the T-group, while bilateral tinnitus dominated in the TH-group from the start (75%). Over time in the T-group, ABR wave V amplitudes (and V/I ratios) remained reduced and delayed. By contrast, in the TH-group especially the ABR wave III and V (and III/I ratio) continued to be enhanced and shortened in response to high-level sound stimuli. Interestingly, in line with signs of an increased co-occurrence of hyperacusis in the T-group over time, ABR wave III also slightly increased in the T-group. The findings disclose an undiagnosed co-occurrence of hyperacusis in tinnitus patients as a main cause of distress and the cause of complaints about tinnitus over time. To achieve urgently needed and personalized therapies, possibly using the objective tools offered here, a systematic sub-classification of tinnitus and the co-occurrence of hyperacusis is recommended.

Real-time monitoring and regulating auditory cortex alpha activity in patients with chronic tinnitus.

OBJECTIVE: Low levels of alpha activity (8-13Hz) mirror a state of enhanced responsiveness, whereas high levels of alpha are a state of reduced responsiveness. Tinnitus is accompanied by reduction of alpha activity in the perisylvian regions compared to normal hearing controls. This reduction might be a key mechanism in the chain of reactions leading to tinnitus. We devised a novel spatial filter as an on-line source monitoring method, which can be used to control alpha activity in the primary auditory cortex. In addition, we designed an innovative experimental procedure to enable suppression of visual and somatosensory alpha, facilitating auditory alpha control during alpha neurofeedback. APPROACH: An amplitude-modulated auditory stimulation with 40 Hz modulation frequency and 1000 Hz carrier frequency specifically activates the primary auditory cortex. The topography of 40 Hz oscillation depicts the activity of the auditory cortices. We used this map as a spatial filter, which passes the activity originating from the auditory cortex. To suppress superposition of auditory alpha by somatosensory and visual alpha, we used a continuous tactile jaw-stimulation and visual stimulation protocol to suppress somatosensory alpha of regions adjacent to the auditory cortex and visual alpha for local regulation of auditory alpha activity only. MAIN RESULTS: This novel spatial filter for online detection of auditory alpha activity and the usage of multi-sensory stimulation facilitate the appearance of alpha activity from the auditory cortex at the sensor level. SIGNIFICANCE: The proposed procedure can be used in an EEG-neurofeedback-treatment approach allowing online auditory alpha self-regulation training in patients with chronic tinnitus.

Enhanced Central Neural Gain Compensates Acoustic Trauma-induced Cochlear Impairment, but Unlikely Correlates with Tinnitus and Hyperacusis.

For successful future therapeutic strategies for tinnitus and hyperacusis, a subcategorization of both conditions on the basis of differentiated neural correlates would be of invaluable advantage. In the present study, we used our refined operant conditioning animal model to divide equally noise-exposed rats into groups with either tinnitus or hyperacusis, with neither condition, or with both conditions co-occurring simultaneously. Using click stimulus and noise burst-evoked Auditory Brainstem Responses (ABR) and Distortion Product Otoacoustic Emissions, no hearing threshold difference was observed between any of the groups. However, animals with neither tinnitus nor hyperacusis responded to noise trauma with shortened ABR wave I and IV latencies and elevated central neuronal gain (increased ABR wave IV/I amplitude ratio), which was previously assumed in most of the literature to be a neural correlate for tinnitus. In contrast, animals with tinnitus had reduced neural response gain and delayed ABR wave I and IV latencies, while animals with hyperacusis showed none of these changes. Preliminary studies, aimed at establishing comparable non-invasive objective tools for identifying tinnitus in humans and animals, confirmed reduced central gain and delayed response latency in human and animals. Moreover, the first ever resting state functional Magnetic Resonance Imaging (rs-fMRI) analyses comparing humans and rats with and without tinnitus showed reduced rs-fMRI activities in the auditory cortex in both patients and animals with tinnitus. These findings encourage further efforts to establish non-invasive diagnostic tools that can be used in humans and animals alike and give hope for differentiated classification of tinnitus and hyperacusis.

Reduced sound-evoked and resting-state BOLD fMRI connectivity in tinnitus.

The exact neurophysiological basis of chronic tinnitus, which affects 10-15% of the population, remains unknown and is controversial at many levels. It is an open question whether phantom sound perception results from increased central neural gain or not, a crucial question for any future therapeutic intervention strategies for tinnitus. We performed a comprehensive study of mild hearing-impaired participants with and without tinnitus, excluding participants with co-occurrences of hyperacusis. A right-hemisphere correlation between tinnitus loudness and auditory perceptual difficulty was observed in the tinnitus group, independent of differences in hearing thresholds. This correlation was linked to reduced and delayed sound-induced suprathreshold auditory brain responses (ABR wave V) in the tinnitus group, suggesting subsided rather than exaggerated central neural responsiveness. When anatomically predefined auditory regions of interest were analysed for altered sound-evoked BOLD fMRI activity, it became evident that subcortical and cortical auditory regions and regions involved in sound detection (posterior insula, hippocampus), responded with reduced BOLD activity in the tinnitus group, emphasizing reduced, rather than increased, central neural gain. Regarding previous findings of evoked BOLD activity being linked to positive connectivities at rest, we additionally analysed r-fcMRI responses in anatomically predefined auditory regions and regions associated with sound detection. A profound reduction in positive interhemispheric connections of homologous auditory brain regions and a decline in the positive connectivities between lower auditory brainstem regions and regions involved in sound detection (hippocampus, posterior insula) were observed in the tinnitus group. The finding went hand-in-hand with the emotional (amygdala, anterior insula) and temporofrontal/stress-regulating regions (prefrontal cortex, inferior frontal gyrus) that were no longer positively connected with auditory cortex regions in the tinnitus group but were instead positively connected to lower-level auditory brainstem regions. Delayed sound processing, reduced sound-evoked BOLD fMRI activity and altered r-fcMRI in the auditory midbrain correlated in the tinnitus group and showed right hemisphere dominance as did tinnitus loudness and perceptual difficulty. The findings suggest that reduced central neural gain in the auditory stream may lead to phantom perception through a failure to energize attentional/stress-regulating networks for contextualization of auditory-specific information. Reduced auditory-specific information flow in tinnitus has until now escaped detection in humans, as low-level auditory brain regions were previously omitted from neuroimaging studies. TRIAL REGISTRATION: German Clinical Trials Register DRKS0006332.

Positioning a Novel Transcutaneous Bone Conduction Hearing Implant: a Systematic Anatomical and Radiological Study to Standardize the Retrosigmoid Approach, Correlating Navigation-guided, and Landmark-based Surgery.

HYPOTHESIS: Anatomical and radiological evaluation improves safety and accuracy of the retrosigmoid approach for positioning a transcutaneous bone conduction implant and provides anatomical reference data for standardized, landmark-based implantation at this alternative site. BACKGROUND: The primary implantation site for the floating mass transducer of a novel bone conduction hearing implant is the mastoid. However, anatomical limitations or previous mastoid surgery may prevent mastoid implantation. Therefore, the retrosigmoid approach has been introduced as an alternative. METHODS: Mastoid and retrosigmoid implantation sites were radiologically identified and evaluated in preoperative computed tomography scans of anatomical head specimens. Navigation-guided implantation was then performed in the retrosigmoid site (n = 20). The optimal retrosigmoid position was determined in relation to both the asterion and the mastoid notch as surgical landmarks in an anatomical coordinate system. RESULTS: Preoperative radiological analysis revealed spatial limitations in the mastoid in 45% of the specimens. Navigation-guided retrosigmoid implantation was possible without affecting the sigmoid sinus in all the specimens. The optimal implantation site was located 1.9 ±â€Š0.1 cm posterior/1.7 ±â€Š0.1 cm inferior to the asterion and 3.3 ±â€Š0.2 cm posterior/2.1 ±â€Š0.1 cm superior to the mastoid notch.Retrosigmoid skull thickness was 6.6 ±â€Š0.4 mm, measured anatomically, 7.0 ±â€Š0.4 mm, measured radiologically and 6.7 ±â€Š0.5 mm, measured with the navigation software. CONCLUSION: The navigation-guided retrosigmoid approach seemed to be a reliable procedure in all the specimens. Measurements of bone thickness revealed the need for spacers in 95% of the specimens. Reference coordinates of the optimal implantation site are provided and can confirm image-guided surgery or facilitate orientation if a navigation system is not available.

The human body odor compound androstadienone leads to anger-dependent effects in an emotional Stroop but not dot-probe task using human faces.

The androgen derivative androstadienone is a substance found in human sweat and thus is a putative human chemosignal. Androstadienone has been studied with respect to effects on mood states, attractiveness ratings, physiological and neural activation. With the current experiment, we aimed to explore in which way androstadienone affects attention to social cues (human faces). Moreover, we wanted to test whether effects depend on specific emotions, the participants' sex and individual sensitivity to smell androstadienone. To do so, we investigated 56 healthy individuals (thereof 29 females taking oral contraceptives) with two attention tasks on two consecutive days (once under androstadienone, once under placebo exposure in pseudorandomized order). With an emotional dot-probe task we measured visuo-spatial cueing while an emotional Stroop task allowed us to investigate interference control. Our results suggest that androstadienone acts in a sex, task and emotion-specific manner as a reduction in interference processes in the emotional Stroop task was only apparent for angry faces in men under androstadienone exposure. More specifically, men showed a smaller difference in reaction times for congruent compared to incongruent trials. At the same time also women were slightly affected by smelling androstadienone as they classified angry faces more often correctly under androstadienone. For the emotional dot-probe task no modulation by androstadienone was observed. Furthermore, in both attention paradigms individual sensitivity to androstadienone was neither correlated with reaction times nor error rates in men and women. To conclude, exposure to androstadienone seems to potentiate the relevance of angry faces in both men and women in connection with interference control, while processes of visuo-spatial cueing remain unaffected.

Absence of Early Neuronal Death in the Olivocochlear System Following Acoustic Overstimulation.

This study was conducted to examine possible effects of noise trauma on olivocochlear (OC) neurons. Anesthetized rats were exposed to a continuous 10 kHz pure tone at 120 dB sound pressure level for 2 hrs. The effects of treatment were verified by recordings of auditory brainstem response and distortion product otoacoustic emission. Three or 8 days after acoustic trauma, rats received unilateral injections of an aqueous solution of the retrograde neuronal tracer Fluorogold (FG) into the scala tympani to identify OC neurons (OCN). Five days after FG injection, brains were perfusion-fixed, and brainstem sections were cut and analyzed with respect to FG-labeled neurons. We found that, in both groups, numbers of OCN were similar to that of controls. The incubation of a second set of sections with antibodies against choline-acetyltransferase (the enzyme responsible for acetylcholine synthesis) showed the cholinergic neurons of the brainstem, however, without suggesting differences between groups. Our study, the first to investigate noise trauma effects on identified OCN, revealed that no visible alterations occurred in 2 weeks following trauma, neither in identified OCN nor in choline-acetyltransferase-immunofluorescence. At this time, auditory brainstem response and distortion product otoacoustic emission measurements showed severe signs of hearing loss. The mechanisms leading to hearing loss upon noise trauma apparently do not involve degeneration of OCN.

Cochlear NMDA receptors as a therapeutic target of noise-induced tinnitus.

BACKGROUND: Accumulating evidence suggests that tinnitus may occur despite normal auditory sensitivity, probably linked to partial degeneration of the cochlear nerve and damage of the inner hair cell (IHC) synapse. Damage to the IHC synapses and deafferentation may occur even after moderate noise exposure. For both salicylate- and noise-induced tinnitus, aberrant N-methyl-d-aspartate (NMDA) receptor activation and related auditory nerve excitation have been suggested as origin of cochlear tinnitus. Accordingly, NMDA receptor inhibition has been proposed as a pharmacologic approach for treatment of synaptopathic tinnitus. METHODS: Round-window application of the NMDA receptor antagonist AM-101 (Esketamine hydrochloride gel; Auris Medical AG, Basel, Switzerland) was tested in an animal model of tinnitus induced by acute traumatic noise. The study included the quantification of IHC ribbon synapses as a correlate for deafferentation as well as the measurement of the auditory brainstem response (ABR) to close-threshold sensation level stimuli as an indication of sound-induced auditory nerve activity. RESULTS: We have shown that AM-101 reduced the trauma-induced loss of IHC ribbons and counteracted the decline of ABR wave I amplitude generated in the cochlea/auditory nerve. CONCLUSION: Local round-window application of AM-101 may be a promising therapeutic intervention for the treatment of synaptopathic tinnitus.

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.

cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function.

Noise-induced hearing loss (NIHL) is a global health hazard with considerable pathophysiological and social consequences that has no effective treatment. In the heart, lung and other organs, cyclic guanosine monophosphate (cGMP) facilitates protective processes in response to traumatic events. We therefore analyzed NIHL in mice with a genetic deletion of the gene encoding cGMP-dependent protein kinase type I (Prkg1) and found a greater vulnerability to and markedly less recovery from NIHL in these mice as compared to mice without the deletion. Prkg1 was expressed in the sensory cells and neurons of the inner ear of wild-type mice, and its expression partly overlapped with the expression profile of cGMP-hydrolyzing phosphodiesterase 5 (Pde5). Treatment of rats and wild-type mice with the Pde5 inhibitor vardenafil almost completely prevented NIHL and caused a Prkg1-dependent upregulation of poly (ADP-ribose) in hair cells and the spiral ganglion, suggesting an endogenous protective cGMP-Prkg1 signaling pathway that culminates in the activation of poly (ADP-ribose) polymerase. These data suggest vardenafil or related drugs as possible candidates for the treatment of NIHL.