Investigating the Effect of Cochlear Synaptopathy on Envelope Following Responses Using a Model of the Auditory Nerve Abstract The healthy auditory system enables communication in challenging situations with high levels of background noise. Yet, despite normal sensitivity to pure tones, many listeners complain about having difficulties in such situations. Recent animal studies demonstrated that noise overexposure that produces temporary threshold shifts can cause the loss of auditory nerve (AN) fiber synapses (i.e., cochlear synaptopathy, CS), which appears to predominantly affect medium- and low-spontaneous rate (SR) fibers. In the present study, envelope following response (EFR) magnitude-level functions were recorded in normal hearing (NH) threshold and mildly hearing-impaired (HI) listeners with thresholds elevated above 2 kHz. EFRs were elicited by sinusoidally amplitude modulated (SAM) tones presented in quiet with a carrier frequency of 2 kHz, modulated at 93 Hz, and modulation depths of 0.85 (deep) and 0.25 (shallow). While EFR magnitude-level functions for deeply modulated tones were similar for all listeners, EFR magnitudes for shallowly modulated tones were reduced at medium stimulation levels in some NH threshold listeners and saturated in all HI listeners for the whole level range. A phenomenological model of the AN was used to investigate the extent to which hair-cell dysfunction and/or CS could explain the trends observed in the EFR data. Hair-cell dysfunction alone, including postulated elevated hearing thresholds at extended high frequencies (EHF) beyond 8 kHz, could not account for the recorded EFR data. Postulated CS led to simulations generally consistent with the recorded data, but a loss of all types of AN fibers was required within the model framework. The effects of off-frequency contributions (i.e., away from the characteristic place of the stimulus) and the differential loss of different AN fiber types on EFR magnitude-level functions were analyzed. When using SAM tones in quiet as the stimulus, model simulations suggested that (1) EFRs are dominated by the activity of high-SR fibers at all stimulus intensities, and (2) EFRs at medium-to-high stimulus levels are dominated by off-frequency contributions.

A Site-Selection Strategy Based on Polarity Sensitivity for Cochlear Implants: Effects on Spectro-Temporal Resolution and Speech Perception ABSTRACT Thresholds of asymmetric pulses presented to cochlear implant (CI) listeners depend on polarity in a way that differs across subjects and electrodes. It has been suggested that lower thresholds for cathodic-dominant compared to anodic-dominant pulses reflect good local neural health. We evaluated the hypothesis that this polarity effect (PE) can be used in a site-selection strategy to improve speech perception and spectro-temporal resolution. Detection thresholds were measured in eight users of Advanced Bionics CIs for 80-pps, triphasic, monopolar pulse trains where the central high-amplitude phase was either anodic or cathodic. Two experimental MAPs were then generated for each subject by deactivating the five electrodes with either the highest or the lowest PE magnitudes (cathodic minus anodic threshold). Performance with the two experimental MAPs was evaluated using two spectro-temporal tests (Spectro-Temporal Ripple for Investigating Processor EffectivenesS (STRIPES; Archer-Boyd et al. in J Acoust Soc Am 144:2983–2997, 2018) and Spectral-Temporally Modulated Ripple Test (SMRT; Aronoff and Landsberger in J Acoust Soc Am 134:EL217–EL222, 2013)) and with speech recognition in quiet and in noise. Performance was also measured with an experimental MAP that used all electrodes, similar to the subjects’ clinical MAP. The PE varied strongly across subjects and electrodes, with substantial magnitudes relative to the electrical dynamic range. There were no significant differences in performance between the three MAPs at group level, but there were significant effects at subject level—not all of which were in the hypothesized direction—consistent with previous reports of a large variability in CI users’ performance and in the potential benefit of site-selection strategies. The STRIPES but not the SMRT test successfully predicted which strategy produced the best speech-in-noise performance on a subject-by-subject basis. The average PE across electrodes correlated significantly with subject age, duration of deafness, and speech perception scores, consistent with a relationship between PE and neural health. These findings motivate further investigations into site-specific measures of neural health and their application to CI processing strategies.

The fMRI Data of Thompson et al. (2006) Do Not Constrain How the Human Midbrain Represents Interaural Time Delay Abstract This commentary provides an alternate interpretation of the fMRI data that were presented in a communication to the journal Nature Neuroscience (Thompson et al., Nat. Neurosci. 9: 1096–1098, 2006 ). The authors argued that their observations demonstrated that traditional models of binaural hearing which incorporate “internal delays,” such as the coincidence-counting mechanism proposed by Jeffress and quantified by Colburn, are invalid, and that a new model for human interaural time delay processing must be developed. We argue that the fMRI data presented do not strongly favor either the refutation or the retention of the traditional models, although they may be useful in constraining the physiological sites of various processing stages. The conclusions of Thompson et al. are based on the locations of maximal activity in the midbrain in response to selected binaural signals. These locations are inconsistent with well-known perceptual attributes of the stimuli under consideration, as is noted by the authors, which suggests that further processing is involved in forming the percept of subjective lateral position.

Exploring the Role of Medial Olivocochlear Efferents on the Detection of Amplitude Modulation for Tones Presented in Noise Abstract The medial olivocochlear reflex has been hypothesized to improve the detection and discrimination of dynamic signals in noisy backgrounds. This hypothesis was tested here by comparing behavioral outcomes with otoacoustic emissions. The effects of a precursor on amplitude-modulation (AM) detection were measured for a 1- and 6-kHz carrier at levels of 40, 60, and 80 dB SPL in a two-octave-wide noise masker with a level designed to produce poor, but above-chance, performance. Three types of precursor were used: a two-octave noise band, an inharmonic complex tone, and a pure tone. Precursors had the same overall level as the simultaneous noise masker that immediately followed the precursor. The noise precursor produced a large improvement in AM detection for both carrier frequencies and at all three levels. The complex tone produced a similarly large improvement in AM detection at the highest level but had a smaller effect for the two lower carrier levels. The tonal precursor did not significantly affect AM detection in noise. Comparisons of behavioral thresholds and medial olivocochlear efferent effects on stimulus frequency otoacoustic emissions measured with similar stimuli did not support the hypothesis that efferent-based reduction of cochlear responses contributes to the precursor effects on AM detection.

Evaluating Psychophysical Polarity Sensitivity as an Indirect Estimate of Neural Status in Cochlear Implant Listeners Abstract The physiological integrity of spiral ganglion neurons is presumed to influence cochlear implant (CI) outcomes, but it is difficult to measure neural health in CI listeners. Modeling data suggest that, when peripheral processes have degenerated, anodic stimulation may be a more effective neural stimulus than cathodic stimulation. The primary goal of the present study was to evaluate the emerging theory that polarity sensitivity reflects neural health in CI listeners. An ideal in vivo estimate of neural integrity should vary independently of other factors known to influence the CI electrode-neuron interface, such as electrode position and tissue impedances. Thus, the present analyses quantified the relationships between polarity sensitivity and (1) electrode position estimated via computed tomography imaging, (2) intracochlear resistance estimated via electrical field imaging, and (3) focused (steered quadrupolar) behavioral thresholds, which are believed to reflect a combination of local neural health, electrode position, and intracochlear resistance. Eleven adults with Advanced Bionics devices participated. To estimate polarity sensitivity, electrode-specific behavioral thresholds in response to monopolar, triphasic pulses where the central high-amplitude phase was either anodic (CAC) or cathodic (ACA) were measured. The polarity effect was defined as the difference in threshold response to the ACA compared to the CAC stimulus. Results indicated that the polarity effect was not related to electrode-to-modiolus distance, electrode scalar location, or intracochlear resistance. Large, positive polarity effects, which may indicate SGN degeneration, were associated with relatively high focused behavioral thresholds. The polarity effect explained a significant portion of the variation in focused thresholds, even after controlling for electrode position and intracochlear resistance. Overall, these results provide support for the theory that the polarity effect may reflect neural integrity in CI listeners. Evidence from this study supports further investigation into the use of polarity sensitivity for optimizing individual CI programming parameters.

Virtual Rhesus Labyrinth Model Predicts Responses to Electrical Stimulation Delivered by a Vestibular Prosthesis Abstract To better understand the spread of prosthetic current in the inner ear and to facilitate design of electrode arrays and stimulation protocols for a vestibular implant system intended to restore sensation after loss of vestibular hair cell function, we created a model of the primate labyrinth. Because the geometry of the implanted ear is complex, accurately modeling effects of prosthetic stimuli on vestibular afferent activity required a detailed representation of labyrinthine anatomy. Model geometry was therefore generated from three-dimensional (3D) reconstructions of a normal rhesus temporal bone imaged using micro-MRI and micro-CT. For systematically varied combinations of active and return electrode location, the extracellular potential field during a biphasic current pulse was computed using finite element methods. Potential field values served as inputs to stochastic, nonlinear dynamic models for each of 2415 vestibular afferent axons, each with unique origin on the neuroepithelium and spiking dynamics based on a modified Smith and Goldberg model. We tested the model by comparing predicted and actual 3D vestibulo-ocular reflex (VOR) responses for eye rotation elicited by prosthetic stimuli. The model was individualized for each implanted animal by placing model electrodes in the standard labyrinth geometry based on CT localization of actual implanted electrodes. Eye rotation 3D axes were predicted from relative proportions of model axons excited within each of the three ampullary nerves, and predictions were compared to archival eye movement response data measured in three alert rhesus monkeys using 3D scleral coil oculography. Multiple empirically observed features emerged as properties of the model, including effects of changing active and return electrode position. The model predicts improved prosthesis performance when the reference electrode is in the labyrinth’s common crus (CC) rather than outside the temporal bone, especially if the reference electrode is inserted nearly to the junction of the CC with the vestibule. Extension of the model to human anatomy should facilitate optimal design of electrode arrays for clinical application.

Neural Encoding of Amplitude Modulations in the Human Efferent System Abstract Most natural sounds, including speech, exhibit temporal amplitude fluctuations. This information is encoded as amplitude modulations (AM)—essential for auditory and speech perception. The neural representation of AM has been studied at various stages of the ascending auditory system from the auditory nerve to the cortex. In contrast, research on neural coding of AM in the efferent pathway has been extremely limited. The objective of this study was to investigate the encoding of AM signals in the medial olivocochlear system by measuring the modulation transfer functions of the efferent response in humans. A secondary goal was to replicate the controversial findings from the literature that efferent stimulation produces larger effects for the AM elicitor with 100 Hz modulation frequency in comparison with the unmodulated elicitor. The efferent response was quantified by measuring changes in stimulus-frequency otoacoustic emission magnitude due to various modulated and unmodulated elicitors. Unmodulated, broadband noise elicitors yielded either slightly larger or similar efferent responses relative to modulated elicitors depending on the modulation frequency. Efferent responses to the unmodulated and modulated elicitors with 100 Hz modulation frequency were not significantly different. The efferent system encoding of AM sounds—modulation transfer functions—can be modeled with a first-order Butterworth low-pass filter with different cutoff frequencies for ipsilateral and contralateral elicitors. The ipsilateral efferent pathway showed a greater sensitivity to AM information comparted to the contralateral pathway. Efferent modulation transfer functions suggest that the ability of the system to follow AM decreases with increasing modulation frequency and that efferents may not be fully operating on the envelope of the speech.

AAV-Mediated Neurotrophin Gene Therapy Promotes Improved Survival of Cochlear Spiral Ganglion Neurons in Neonatally Deafened Cats: Comparison of AAV2-hBDNF and AAV5-hGDNF Abstract Outcomes with contemporary cochlear implants (CI) depend partly upon the survival and condition of the cochlear spiral ganglion (SG) neurons. Previous studies indicate that CI stimulation can ameliorate SG neural degeneration after deafness, and brain-derived neurotrophic factor (BDNF) delivered by an osmotic pump can further improve neural survival. However, direct infusion of BDNF elicits undesirable side effects, and osmotic pumps are impractical for clinical application. In this study, we explored the potential for two adeno-associated viral vectors (AAV) to elicit targeted neurotrophic factor expression in the cochlea and promote improved SG and radial nerve fiber survival. Juvenile cats were deafened prior to hearing onset by systemic aminoglycoside injections. Auditory brainstem responses showed profound hearing loss by 16–18 days postnatal. At ~ 4 weeks of age, AAV2-GFP (green fluorescent protein), AAV5-GFP, AAV2-hBDNF, or AAV5-hGDNF (glial-derived neurotrophic factor) was injected through the round window unilaterally. For GFP immunofluorescence, animals were studied ~ 4 weeks post-injection to assess cell types transfected and their distributions. AAV2-GFP immunofluorescence demonstrated strong expression of the GFP reporter gene in residual inner (IHCs), outer hair cells (OHCs), inner pillar cells, and in some SG neurons throughout the cochlea. AAV5-GFP elicited robust transduction of IHCs and some SG neurons, but few OHCs and supporting cells. After AAV-neurotrophic factor injections, animals were studied ~ 3 months post-injection to evaluate neural survival. AAV5-hGDNF elicited a modest neurotrophic effect, with 6 % higher SG density, but had no trophic effect on radial nerve fiber survival, and undesirable ectopic fiber sprouting occurred. AAV2-hBDNF elicited a similar 6 % increase in SG survival, but also resulted in greatly improved radial nerve fiber survival, with no ectopic fiber sprouting. A further study assessed whether AAV2-hBDNF neurotrophic effects would persist over longer post-injection periods. Animals examined 6 months after virus injection showed substantial neurotrophic effects, with 14 % higher SG density and greatly improved radial nerve fiber survival. Our results suggest that AAV-neurotrophin gene therapy can elicit expression of physiological concentrations of neurotrophins in the cochlea, supporting improved SG neuronal and radial nerve fiber survival while avoiding undesirable side effects. These studies also demonstrate the potential for application of cochlear gene therapy in a large mammalian cochlea comparable to the human cochlea and in an animal model of congenital/early acquired deafness.

Quantitative Assessment of Anti-Gravity Reflexes to Evaluate Vestibular Dysfunction in Rats Abstract The tail-lift reflex and the air-righting reflex are anti-gravity reflexes in rats that depend on vestibular function. To obtain objective and quantitative measures of performance, we recorded these reflexes with slow-motion video in two experiments. In the first experiment, vestibular dysfunction was elicited by acute exposure to 0 (control), 400, 600, or 1000 mg/kg of 3,3′-iminodipropionitrile (IDPN), which causes dose-dependent hair cell degeneration. In the second, rats were exposed to sub-chronic IDPN in the drinking water for 0 (control), 4, or 8 weeks; this causes reversible or irreversible loss of vestibular function depending on exposure time. In the tail-lift test, we obtained the minimum angle defined during the lift and descent maneuver by the nose, the back of the neck, and the base of the tail. In the air-righting test, we obtained the time to right the head. We also obtained vestibular dysfunction ratings (VDRs) using a previously validated behavioral test battery. Each measure, VDR, tail-lift angle, and air-righting time demonstrated dose-dependent loss of vestibular function after acute IDPN and time-dependent loss of vestibular function after sub-chronic IDPN. All measures showed high correlations between each other, and maximal correlation coefficients were found between VDRs and tail-lift angles. In scanning electron microscopy evaluation of the vestibular sensory epithelia, the utricle and the saccule showed diverse pathological outcomes, suggesting that they have a different role in these reflexes. We conclude that these anti-gravity reflexes provide useful objective and quantitative measures of vestibular function in rats that are open to further development.

Pre-operative Brain Imaging Using Functional Near-Infrared Spectroscopy Helps Predict Cochlear Implant Outcome in Deaf Adults Abstract Currently, it is not possible to accurately predict how well a deaf individual will be able to understand speech when hearing is (re)introduced via a cochlear implant. Differences in brain organisation following deafness are thought to contribute to variability in speech understanding with a cochlear implant and may offer unique insights that could help to more reliably predict outcomes. An emerging optical neuroimaging technique, functional near-infrared spectroscopy (fNIRS), was used to determine whether a pre-operative measure of brain activation could explain variability in cochlear implant (CI) outcomes and offer additional prognostic value above that provided by known clinical characteristics. Cross-modal activation to visual speech was measured in bilateral superior temporal cortex of pre- and post-lingually deaf adults before cochlear implantation. Behavioural measures of auditory speech understanding were obtained in the same individuals following 6 months of cochlear implant use. The results showed that stronger pre-operative cross-modal activation of auditory brain regions by visual speech was predictive of poorer auditory speech understanding after implantation. Further investigation suggested that this relationship may have been driven primarily by the inclusion of, and group differences between, pre- and post-lingually deaf individuals. Nonetheless, pre-operative cortical imaging provided additional prognostic value above that of influential clinical characteristics, including the age-at-onset and duration of auditory deprivation, suggesting that objectively assessing the physiological status of the brain using fNIRS imaging pre-operatively may support more accurate prediction of individual CI outcomes. Whilst activation of auditory brain regions by visual speech prior to implantation was related to the CI user’s clinical history of deafness, activation to visual speech did not relate to the future ability of these brain regions to respond to auditory speech stimulation with a CI. Greater pre-operative activation of left superior temporal cortex by visual speech was associated with enhanced speechreading abilities, suggesting that visual speech processing may help to maintain left temporal lobe specialisation for language processing during periods of profound deafness.