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Attention plays an important role in not only the awareness and perception of tinnitus but also its interactions with external sounds. Recent evidence suggests that attention is heightened in the tinnitus brain, likely as a result of relatively local cortical changes specific to deafferentation sites or global changes that help maintain normal cognitive capabilities in individuals with hearing loss. However, most electrophysiological studies have used passive listening paradigms to probe the tinnitus brain and produced mixed results in terms of finding a distinctive biomarker for tinnitus. Here, we designed a selective attention task, in which human adults attended to one of two interleaved tonal (500 Hz and 5 kHz) sequences. In total, 16 tinnitus (5 females) and 13 age- and hearing-matched control (8 females) subjects participated in the study, with the tinnitus subjects matching the tinnitus pitch to 5.4 kHz (range = 1.9-10.8 kHz). Cortical responses were recorded in both passive and attentive listening conditions, producing no differences in P1, N1, and P2 between the tinnitus and control subjects under any conditions. However, a different pattern of results emerged when the difference was examined between the attended and unattended responses. This attention-modulated cortical response was significantly greater in the tinnitus than control subjects: 3.9-times greater for N1 at 5 kHz (95% CI: 2.9 to 5.0, p = 0.007, ηp2 = 0.24) and 3.0 for P2 at 500 Hz (95% CI: 1.9 to 4.5, p = 0.026, ηp2 = 0.17). We interpreted the greater N1 modulation as local neural changes specific to the tinnitus frequency and the greater P2 as global changes to hearing loss. These two cortical measures were used to differentiate between the tinnitus and control subjects, producing 83.3% sensitivity and 76.9% specificity (AUC = 0.81, p = 0.006). These results suggest that the tinnitus brain is more plastic than that of the matched non-tinnitus controls and that the attention-modulated cortical response can be developed as a clinically meaningful biomarker for tinnitus.

IntroductionObjectively predicting speech intelligibility is important in both telecommunication and human-machine interaction systems. The classic method relies on signal-to-noise ratios (SNR) to successfully predict speech intelligibility. One exception is clear speech, in which a talker intentionally articulates as if speaking to someone who has hearing loss or is from a different language background. As a result, at the same SNR, clear speech produces higher intelligibility than conversational speech. Despite numerous efforts, no objective metric can successfully predict the clear speech benefit at the sentence level.MethodsWe proposed a Syllable-Rate-Adjusted-Modulation (SRAM) index to predict the intelligibility of clear and conversational speech. The SRAM used as short as 1 s speech and estimated its modulation power above the syllable rate. We compared SRAM with three reference metrics: envelope-regression-based speech transmission index (ER-STI), hearing-aid speech perception index version 2 (HASPI-v2) and short-time objective intelligibility (STOI), and five automatic speech recognition systems: Amazon Transcribe, Microsoft Azure Speech-To-Text, Google Speech-To-Text, wav2vec2 and Whisper.ResultsSRAM outperformed the three reference metrics (ER-STI, HASPI-v2 and STOI) and the five automatic speech recognition systems. Additionally, we demonstrated the important role of syllable rate in predicting speech intelligibility by comparing SRAM with the total modulation power (TMP) that was not adjusted by the syllable rate.DiscussionSRAM can potentially help understand the characteristics of clear speech, screen speech materials with high intelligibility, and convert conversational speech into clear speech.

Mechanistic insight is achieved only when experiments are employed to test formal or computational models. Furthermore, in analogy to lesion studies, phantom perception may serve as a vehicle to understand the fundamental processing principles underlying healthy auditory perception. With a special focus on tinnitus-as the prime example of auditory phantom perception-we review recent work at the intersection of artificial intelligence, psychology and neuroscience. In particular, we discuss why everyone with tinnitus suffers from (at least hidden) hearing loss, but not everyone with hearing loss suffers from tinnitus. We argue that intrinsic neural noise is generated and amplified along the auditory pathway as a compensatory mechanism to restore normal hearing based on adaptive stochastic resonance. The neural noise increase can then be misinterpreted as auditory input and perceived as tinnitus. This mechanism can be formalized in the Bayesian brain framework, where the percept (posterior) assimilates a prior prediction (brain's expectations) and likelihood (bottom-up neural signal). A higher mean and lower variance (i.e. enhanced precision) of the likelihood shifts the posterior, evincing a misinterpretation of sensory evidence, which may be further confounded by plastic changes in the brain that underwrite prior predictions. Hence, two fundamental processing principles provide the most explanatory power for the emergence of auditory phantom perceptions: predictive coding as a top-down and adaptive stochastic resonance as a complementary bottom-up mechanism. We conclude that both principles also play a crucial role in healthy auditory perception. Finally, in the context of neuroscience-inspired artificial intelligence, both processing principles may serve to improve contemporary machine learning techniques.

This diagnostic study assesses the performance of the Apple Watch Noise application in comparison with a class 1 sound level meter.

Use of artificial intelligence (AI) is a burgeoning field in otolaryngology and the communication sciences. A virtual symposium on the topic was convened from Duke University on October 26, 2020, and was attended by more than 170 participants worldwide. This review presents summaries of all but one of the talks presented during the symposium; recordings of all the talks, along with the discussions for the talks, are available at https://www.youtube.com/watch?v=ktfewrXvEFg and https://www.youtube.com/watch?v=-gQ5qX2v3rg . Each of the summaries is about 2500 words in length and each summary includes two figures. This level of detail far exceeds the brief summaries presented in traditional reviews and thus provides a more-informed glimpse into the power and diversity of current AI applications in otolaryngology and the communication sciences and how to harness that power for future applications.

While noninvasive brain stimulation is convenient and cost effective, its utility is limited by the substantial distance between scalp electrodes and their intended neural targets in the head. The tympanic membrane, or eardrum, is a thin flap of skin deep in an orifice of the head that may serve as a port for improved efficiency of noninvasive stimulation. Here we chose the cochlea as a target because it resides in the densest bone of the skull and is adjacent to many deep-brain-stimulation structures. We also tested the hypothesis that noninvasive electric stimulation of the cochlea may restore neural activities that are missing in acoustic stimulation. We placed an electrode in the ear canal or on the tympanic membrane in 25 human adults (10 females) and compared their stimulation efficiency by characterizing the electrically-evoked auditory sensation. Relative to ear canal stimulation, tympanic membrane stimulation was four times more likely to produce an auditory percept, required eight times lower electric current to reach the threshold and produced two-to-four times more linear suprathreshold responses. We further measured tinnitus suppression in 14 of the 25 subjects who had chronic tinnitus. Compared with ear canal stimulation, tympanic membrane stimulation doubled both the probability (22% vs. 55%) and the amount (-15% vs. -34%) of tinnitus suppression. These findings extended previous work comparing evoked perception and tinnitus suppression between electrodes placed in the ear canal and on the scalp. Together, the previous and present results suggest that the efficiency of conventional scalp-based noninvasive electric stimulation can be improved by at least one order of magnitude via tympanic membrane stimulation. This increased efficiency is most likely due to the shortened distance between the electrode placed on the tympanic membrane and the targeted cochlea. The present findings have implications for the management of tinnitus by offering a potential alternative to interventions using invasive electrical stimulation such as cochlear implantation, or other non-invasive transcranial electrical stimulation methods.

Animal studies have discovered that noise, even at levels that produce no permanent threshold shift, may cause cochlear damage and selective nerve degeneration. A hallmark of such damage, or synaptopathy, is recovered threshold but reduced suprathreshold amplitude for the auditory brainstem response (ABR) wave I. The objective of the present study is to evaluate whether the ABR wave I amplitude or slope can be used to diagnose tinnitus in humans. A total of 43 human subjects, consisting of 21 with tinnitus and 22 without tinnitus, participated in the study. The subjects were on average 44 ± 24 (standard deviation) years old and 16 were female; a subgroup of 19 were young adults with normal audiograms from 125 to 8000 Hz. The ABR was measured using ear canal recording tiptrodes for clicks, 1000, 4000 and 8000 Hz tone bursts at 30, 50, and 70 dB nHL. Compared with control subjects, tinnitus subjects did not show reduced ABR wave I amplitude or slope in either the entire group of 21 tinnitus subjects or a subset of tinnitus subjects with normal audiograms. Despite the small sample size and diverse tinnitus population, the present result suggests that low signal-to-noise ratios in non-invasive measurement of the ABR limit its clinical utility in diagnosing tinnitus in humans.

ObjectivesElectric stimulation is used to treat a number of neurologic disorders such as epilepsy and depression. However, delivering the required current to far-field neural targets is often ineffective because of current spread through low-impedance pathways. Here, the specific aims are to develop an empirical measure for current passing through the human head and to optimize stimulation strategies for targeting deeper structures, including the auditory nerve, by utilizing the cochlear implant (CI).Materials and methodsOutward input/output (I/O) functions were obtained by CI stimulation and recording scalp potentials in five CI subjects. Conversely, inward I/O functions were obtained by noninvasive transcranial electric stimulation (tES) and recording intracochlear potentials using the onboard recording capability of the CI.ResultsI/O measures indicate substantial current spread, with a maximum of 2.2% gain recorded at the inner ear target during tES (mastoid-to-mastoid electrode configuration). Similarly, CI stimulation produced a maximum of 1.1% gain at the scalp electrode nearest the CI return electrode. Gain varied with electrode montage according to a point source model that accounted for distances between the stimulating and recording electrodes. Within the same electrode montages, current gain patterns varied across subjects suggesting the importance of tissue properties, geometry, and electrode positioning.ConclusionThese results provide a novel objective measure of electric stimulation in the human head, which can help to optimize stimulation parameters that improve neural excitation of deep structures by reducing the influence of current spread.Conflict of interestThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Wenhui Mao and coauthors discuss possible implications of the COVID-19 pandemic for health aspirations in low- and middle-income countries.

Electrophysiological studies show that nicotine enhances neural responses to characteristic frequency stimuli. Previous behavioral studies partially corroborate these findings in young adults, showing that nicotine selectively enhances auditory processing in difficult listening conditions. The present work extended previous work to include both young and older adults and assessed the nicotine effect on sound frequency and intensity discrimination. Hypotheses were that nicotine improves auditory performance and that the degree of improvement is inversely proportional to baseline performance. Young (19-23 years old) normal-hearing nonsmokers and elderly (61-80) nonsmokers with normal hearing between 500 and 2000 Hz received nicotine gum (6 mg) or placebo gum in a single-blind, randomized crossover design. Participants performed three experiments (frequency discrimination, frequency modulation identification, and intensity discrimination) before and after treatment. The perceptual differences were analyzed between pre- and post-treatment, as well as between post-treatment nicotine and placebo conditions as a function of pre-treatment baseline performance. Compared to pre-treatment performance, nicotine significantly improved frequency discrimination. Compared to placebo, nicotine significantly improved performance for intensity discrimination, and the improvement was more pronounced in the elderly with lower baseline performance. Nicotine had no effect on frequency modulation identification. Nicotine effects are task-dependent, reflecting possible interplays of subjects, tasks and neural mechanisms.

Because hearing loss is a high-risk factor for cognitive decline, tinnitus, a comorbid condition of hearing loss, is often presumed to impair cognition. The present cross-sectional study aimed to delineate the interaction of tinnitus and cognition in the elderly with and without hearing loss after adjusting for covariates in race, age, sex, education, pure tone average, hearing aids, and physical well-being. Participants included 643 adults (60-69 years old; 51.3% females) from the National Health and Nutrition Examination Survey (NHANES, 2011-2012), and 1,716 (60-69 years old; 60.4% females) from the Hispanic Community Health Study (HCHS, 2008-2011). Multivariable linear and binary logistic regression was used to assess the association between tinnitus and cognition in the two sub-cohorts of normal hearing (NHANES, n = 508; HCHS, n = 1264) and hearing loss (NHANES, n = 135; HCHS, n = 453). Cognitive performance was measured as a composite z-score from four cognitive tests: The Consortium to Establish a Registry for Alzheimers Disease (CERAD)-word learning, CERAD-animal fluency, CERAD-word list recall, and the digit symbol substitution test (DSST) in NHANES, and a comparable Hispanic version of these four tests in HCHS. Multivariable linear regression revealed no association between tinnitus and cognition, except for the NHANES (non-Hispanic) participants with hearing loss, where the presence of tinnitus was associated with improved cognitive performance (Mean = 0.3; 95% CI, 0.1-0.5; p, 0.018). Using the 25th percentile score of the control (i.e., normal hearing and no tinnitus) as a threshold for poor cognitive performance, the absence of tinnitus increased the risk for poor cognitive performance (OR = 5.6, 95% CI, 1.9-17.2; p, 0.002). Sensitivity analysis found a positive correlation between tinnitus duration and cognitive performance in the NHANES cohort [F(4,140), 2.6; p, 0.037]. The present study finds no evidence for the assumption that tinnitus impairs cognitive performance in the elderly. On the contrary, tinnitus is associated with improved cognitive performance in the non-Hispanic elderly with hearing loss. The present result suggests that race be considered as an important and relevant factor in the experimental design of tinnitus research. Future longitudinal and imaging studies are needed to validate the present findings and understand their mechanisms.

The importance of tele-audiology has been heightened by the current COVID-19 pandemic. The present article reviews the current state of tele-audiology practice while presenting its limitations and opportunities. Specifically, this review addresses: (1) barriers to hearing healthcare, (2) tele-audiology services, and (3) tele-audiology key issues, challenges, and future directions. Accumulating evidence suggests that tele-audiology is a viable service delivery model, as remote hearing screening, diagnostic testing, intervention, and rehabilitation can each be completed reliably and effectively. The benefits of tele-audiology include improved access to care, increased follow-up rates, and reduced travel time and costs. Still, significant logistical and technical challenges remain from ensuring a secure and robust internet connection to controlling ambient noise and meeting all state and federal licensure and reimbursement regulations. Future research and development, especially advancements in artificial intelligence, will continue to increase tele-audiology acceptance, expand remote care, and ultimately improve patient satisfaction.

Tinnitus is a phantom auditory sensation in the absence of external sounds, while hyperacusis is an atypical sensitivity to external sounds that leads them to be perceived as abnormally loud or even painful. Both conditions may reflect the brain's over-compensation for reduced input from the ear. The present work differentiates between two compensation models: The additive central noise compensates for hearing loss and is likely to generate tinnitus, whereas the multiplicative central gain compensates for hidden hearing loss and is likely to generate hyperacusis. Importantly, both models predict increased variance in central representations of sounds, especially a nonlinear increase in variance by the central gain. The increased central variance limits the amount of central compensation and reduces temporal synchrony, which can explain the insufficient central gain reported in the literature. Future studies need to collect trial-by-trial firing variance data so that the present variance-based model can be falsified.

To examine difficulties experienced by cochlear implant (CI) users when perceiving non-native speech, intelligibility of non-native speech was compared in conditions with single and multiple alternating talkers. Compared to listeners with normal hearing, no rapid talker-dependent adaptation was observed and performance was approximately 40% lower for CI users following increased exposure in both talker conditions. Results suggest that lower performance for CI users may stem from combined effects of limited spectral resolution, which diminishes perceptible differences across accents, and limited access to talker-specific acoustic features of speech, which reduces the ability to adapt to non-native speech in a talker-dependent manner.

Tinnitus is a sound heard by 15% of the general population in the absence of any external sound. Because external sounds can sometimes mask tinnitus, tinnitus is assumed to affect the perception of external sounds, leading to hypotheses such as "tinnitus filling in the temporal gap" in animal models and "tinnitus inducing hearing difficulty" in human subjects. Here we compared performance in temporal, spectral, intensive, masking and speech-in-noise perception tasks between 45 human listeners with chronic tinnitus (18 females and 27 males with a range of ages and degrees of hearing loss) and 27 young, normal-hearing listeners without tinnitus (11 females and 16 males). After controlling for age, hearing loss, and stimulus variables, we discovered that, contradictory to the widely held assumption, tinnitus does not interfere with the perception of external sounds in 32 of the 36 measures. We interpret the present result to reflect a bottom-up pathway for the external sound and a separate top-down pathway for tinnitus. We propose that these two perceptual pathways can be independently modulated by attention, which leads to the asymmetrical interaction between external and internal sounds, and several other puzzling tinnitus phenomena such as discrepancy in loudness between tinnitus rating and matching. The present results suggest not only a need for new theories involving attention and central noise in animal tinnitus models but also a shift in focus from treating tinnitus to managing its comorbid conditions when addressing complaints about hearing difficulty in individuals with tinnitus.SIGNIFICANCE STATEMENT Tinnitus, or ringing in the ears, is a neurologic disorder that affects 15% of the general population. Here we discovered an asymmetrical relationship between tinnitus and external sounds: although external sounds have been widely used to cover up tinnitus, tinnitus does not impair, and sometimes even improves, the perception of external sounds. This counterintuitive discovery contradicts the general belief held by scientists, clinicians, and even individuals with tinnitus themselves, who often report hearing difficulty, especially in noise. We attribute the counterintuitive discovery to two independent pathways: the bottom-up perception of external sounds and the top-down perception of tinnitus. Clinically, the present work suggests a shift in focus from treating tinnitus itself to treating its comorbid conditions and secondary effects.

RATIONALE: Electrophysiological studies show that systemic nicotine narrows frequency receptive fields and increases gain in neural responses to characteristic frequency stimuli. We postulated that nicotine enhances related auditory processing in humans. OBJECTIVES: The main hypothesis was that nicotine improves auditory performance. A secondary hypothesis was that the degree of nicotine-induced improvement depends on the individuals baseline performance. METHODS: Young (18-27 years old), normal-hearing nonsmokers received nicotine (Nicorette gum, 6mg) or placebo gum in a single-blind, randomized, crossover design. Subjects performed four experiments involving tone-in-noise detection, temporal gap detection, spectral ripple discrimination, and selective auditory attention before and after treatment. The perceptual differences between posttreatment nicotine and placebo conditions were measured and analyzed as a function of the pre-treatment baseline performance. RESULTS: Nicotine significantly improved performance in the more difficult tasks of tone-in-noise detection and selective attention (effect size = - 0.3) but had no effect on relatively easier tasks of temporal gap detection and spectral ripple discrimination. The two tasks showing significant nicotine effects further showed no baseline-dependent improvement. CONCLUSIONS: Nicotine improves auditory performance in difficult listening situations. The present results support future investigation of nicotine effects in clinical populations with auditory processing deficits or reduced cholinergic activation.

ObjectivesElectro-acoustic stimulation (EAS) enhances speech and music perception in cochlear-implant (CI) users who have residual low-frequency acoustic hearing. For CI users who do not have low-frequency acoustic hearing, tactile stimulation may be used in a similar fashion as residual low-frequency acoustic hearing to enhance CI performance. Previous studies showed that electro-tactile stimulation (ETS) enhanced speech recognition in noise and tonal language perception for CI listeners. Here, we examined the effect of ETS on melody recognition in both musician and nonmusician CI users.DesignNine musician and eight nonmusician CI users were tested in a melody recognition task with or without rhythmic cues in three testing conditions: CI only (E), tactile only (T), and combined CI and tactile stimulation (ETS).ResultsOverall, the combined electrical and tactile stimulation enhanced the melody recognition performance in CI users by 9% points. Two additional findings were observed. First, musician CI users outperformed nonmusicians CI users in melody recognition, but the size of the enhancement effect was similar between the two groups. Second, the ETS enhancement was significantly higher with nonrhythmic melodies than rhythmic melodies in both groups.ConclusionsThese findings suggest that, independent of musical experience, the size of the ETS enhancement depends on integration efficiency between tactile and auditory stimulation, and that the mechanism of the ETS enhancement is improved electric pitch perception. The present study supports the hypothesis that tactile stimulation can be used to improve pitch perception in CI users.

Psychophysical laws quantitatively relate perceptual magnitude to stimulus intensity. While most people have accepted Stevens's power function as the psychophysical law, few believe in Fechner's original idea using just-noticeable-differences (jnd) as a constant perceptual unit to educe psychophysical laws. Here I present a unified theory in hearing, starting with a general form of Zwislocki's loudness function (1965) to derive a general form of Brentano's law. I will arrive at a general form of the loudness-jnd relationship that unifies previous loudness-jnd theories. Specifically, the "slope," "proportional-jnd," and "equal-loudness, equal-jnd" theories, are three additive terms in the new unified theory. I will also show that the unified theory is consistent with empirical data in both acoustic and electric hearing. Without any free parameters, the unified theory uses loudness balance functions to successfully predict the jnd function in a wide range of hearing situations. The situations include loudness recruitment and its jnd functions in sensorineural hearing loss and simultaneous masking, loudness enhancement and the midlevel hump in forward and backward masking, abnormal loudness and jnd functions in cochlear implant subjects. Predictions of these loudness-jnd functions were thought to be questionable at best in simultaneous masking or not possible at all in forward masking. The unified theory and its successful applications suggest that although the specific form of Fechner's law needs to be revised, his original idea is valid in the wide range of hearing situations discussed here.

ObjectivesElectric stimulation is used to treat a number of neurologic disorders such as epilepsy and depression. However, delivering the required current to far-field neural targets is often ineffective because of current spread through low-impedance pathways. Here, the specific aims are to develop an empirical measure for current passing through the human head and to optimize stimulation strategies for targeting deeper structures, including the auditory nerve, by utilizing the cochlear implant (CI).Materials and methodsOutward input/output (I/O) functions were obtained by CI stimulation and recording scalp potentials in five CI subjects. Conversely, inward I/O functions were obtained by noninvasive transcranial electric stimulation (tES) and recording intracochlear potentials using the onboard recording capability of the CI.ResultsI/O measures indicate substantial current spread, with a maximum of 2.2% gain recorded at the inner ear target during tES (mastoid-to-mastoid electrode configuration). Similarly, CI stimulation produced a maximum of 1.1% gain at the scalp electrode nearest the CI return electrode. Gain varied with electrode montage according to a point source model that accounted for distances between the stimulating and recording electrodes. Within the same electrode montages, current gain patterns varied across subjects suggesting the importance of tissue properties, geometry, and electrode positioning.ConclusionThese results provide a novel objective measure of electric stimulation in the human head, which can help to optimize stimulation parameters that improve neural excitation of deep structures by reducing the influence of current spread.

Noninvasive transcranial electric stimulation is increasingly being used as an advantageous therapy alternative that may activate deep tissues while avoiding drug side-effects. However, not only is there limited evidence for activation of deep tissues by transcranial electric stimulation, its evoked human sensation is understudied and often dismissed as a placebo or secondary effect. By systematically characterizing the human sensation evoked by transcranial alternating-current stimulation, we observed not only stimulus frequency and electrode position dependencies specific for auditory and visual sensation but also a broader presence of somatic sensation ranging from touch and vibration to pain and pressure. We found generally monotonic input-output functions at suprathreshold levels, and often multiple types of sensation occurring simultaneously in response to the same electric stimulation. We further used a recording circuit embedded in a cochlear implant to directly and objectively measure the amount of transcranial electric stimulation reaching the auditory nerve, a deep intercranial target located in the densest bone of the skull. We found an optimal configuration using an ear canal electrode and low-frequency (

BackgroundDeep brain stimulation (DBS) can be an effective therapy for tics and comorbidities in select cases of severe, treatment-refractory Tourette syndrome (TS). Clinical responses remain variable across patients, which may be attributed to differences in the location of the neuroanatomical regions being stimulated. We evaluated active contact locations and regions of stimulation across a large cohort of patients with TS in an effort to guide future targeting.MethodsWe collected retrospective clinical data and imaging from 13 international sites on 123 patients. We assessed the effects of DBS over time in 110 patients who were implanted in the centromedial (CM) thalamus (n=51), globus pallidus internus (GPi) (n=47), nucleus accumbens/anterior limb of the internal capsule (n=4) or a combination of targets (n=8). Contact locations (n=70 patients) and volumes of tissue activated (n=63 patients) were coregistered to create probabilistic stimulation atlases.ResultsTics and obsessive-compulsive behaviour (OCB) significantly improved over time (p0.05). The median time was 13 months to reach a 40% improvement in tics, and there were no significant differences across targets (p=0.84), presence of OCB (p=0.09) or age at implantation (p=0.08). Active contacts were generally clustered near the target nuclei, with some variability that may reflect differences in targeting protocols, lead models and contact configurations. There were regions within and surrounding GPi and CM thalamus that improved tics for some patients but were ineffective for others. Regions within, superior or medial to GPi were associated with a greater improvement in OCB than regions inferior to GPi.ConclusionThe results collectively indicate that DBS may improve tics and OCB, the effects may develop over several months, and stimulation locations relative to structural anatomy alone may not predict response. This study was the first to visualise and evaluate the regions of stimulation across a large cohort of patients with TS to generate new hypotheses about potential targets for improving tics and comorbidities.

OBJECTIVE: To improve the existing manually assembled cochlear implant electrode arrays, a thin-film electrode array (TFEA) was microfabricated having a maximum electrode density of 15 sites along an 8-mm length, with each site having a 75 μm × 1.8 μm (diameter × height) disk electrode. METHODS: The microfabrication method adopted photoresist transferring, lift-off, two-step oxygen plasma etching, and fuming nitric acid release to reduce lift-off complexity, protect the metal layer, and increase the release efficiency. RESULTS: Systematic in vitro characterization showed that the TFEAs bending stiffness was 6.40 × 10-10 N·m2 near the base and 1.26 × 10-10 N·m2 near the apex. The TFEA electrode produced an average impedance of 16 kΩ and a maximum current limit of 800 μA, measured with 1-kHz sinusoidal current using monopolar stimulation in saline. A TFEA prototype was implanted in a cat cochlea to obtain in vivo measurements of electrically evoked auditory brainstem and inferior colliculus responses to monopolar stimulation with 41-μs/phase biphasic pulses. Both physiological responses produced a threshold of ∼300 μA and a dynamic range of 5-8 dB above the threshold. Compared with existing arrays, the present TFEA had 104 times less bending stiffness, 97% less electrode area, and comparable physiological thresholds. CONCLUSION: Using a simplified structure and stable fabrication method, the present TEFA produced physical and physiological performance comparable to existing commercial devices. SIGNIFICANCE: The present TFEA represents a step closer toward an automated process replacing the labor-intensive and expensive manual assembly of the cochlear implant electrode arrays.

Noninvasive transcranial or minimally invasive transtympanic electric stimulation may offer a desirable treatment option for tinnitus because it can activate the deafferented auditory nerve fibers while posing little to no risk to hearing. Here, we built a flexible research interface to generate and control accurately charge-balanced current stimulation as well as a head-mounted instrument capable of holding a transtympanic electrode steady for hours. We then investigated the short-term effect of a limited set of electric stimulation parameters on tinnitus in 10 adults with chronic tinnitus. The preliminary results showed that 63% of conditions of electric stimulation produced some degree of tinnitus reduction, with total disappearance of tinnitus in six subjects in response to at least one condition. The present study also found significant side effects such as visual, tactile, and even pain sensations during electric stimulation. In addition to masking and residual inhibition, neuroplasticity is likely involved in the observed tinnitus reduction. To translate the present electric stimulation into a safe and effective tinnitus treatment option, we need to optimize stimulation parameters that activate the deafferented auditory nerve fibers and reliably suppress tinnitus, with minimal side effects and tolerable sensations. Noninvasive or minimally invasive electric stimulation can be integrated with sound therapy, invasive cochlear implants, or other forms of coordinated stimulation to provide a systematic strategy for tinnitus treatment or even a cure.

As the only medical device used in the treatment for deafness, the cochlear implant has benefited to more than half a million individuals worldwide. However, the device has limited penetration due to its high cost, especially in low- and middle-income countries. China alone has 27.8 million deaf people, but less than 100,000 of them have received a cochlear implant. The Nurotron Venus device was developed to address the need for an affordable yet safe and effective cochlear implant. The present study describes the design, development, and evaluation of the Nurotron intracochlear electrode array. The standard array is 22 mm in length from the round window marker to the apical tip of the carrier and has 24 electrodes, with a surface area of 0.32 mm2 and center-to-center spacing of 0.85 mm. The Nurotron array has been tested to meet the mechanical, chemical, and electrical requirements specified by the ISO Standard 14708-07. Human temporal bone and clinical trial results showed that the Nurotron array is easy to insert (7.8/10 rating with 10 indicating the highest ease of use) and has a low complication rate (12.5%) of severe insertion trauma while achieving high device stability and reliability (6 array failures in 43,000 patient years of experience). As a critical component, the Nurotron array has contributed to the high level of Nurotron implant speech performance, equivalent to that produced by other existing devices. The Nurotron device has benefited 10,000 deaf people and helped reduce the unit cost from US$25,000 in 2011 to US$4,620 in 2017 through the Chinese Government Tender Program. New, slim, and micromachined electrodes are being developed to further improve performance and accessibility.

The micro-fabricated thin film electrode array (TFEA) has been a promising design for cochlear implants (CIs) because of its cost-effectiveness and fabrication precision. The latest polymer-based cochlear TFEAs have faced difficulties for cochlear insertion due to the lack of structural stiffness. To stiffen the TFEA, dissolvable stiffening materials, TFEAs with different structures, and TFEAs with commercial CIs as carriers have been invested. In this work, the concept of enhancing a Parylene TFEA with Kapton tape as a simpler carrier for cochlear insertion has been proved to be feasible. The bending stiffness of the Kapton-aided TFEA was characterized with an analytical model, a finite element model, and a cantilever bending experiment, respectively. While the Kapton tape increased the bending stiffness of the Parylene TFEA by 10³ times, the 6-μm-thick TFEA with a similar Young's modulus, as a polyimide, in turn significantly increased the bending stiffness of the 170-μm-thick Kapton carrier by 60%. This result indicated that even the TFEA is ultra-flexible and that its bending stiffness should not be neglected in the design or selection of its carrier.

ObjectiveElectro-acoustic stimulation (EAS) is an effective method to enhance cochlear-implant performance in individuals who have residual low-frequency acoustic hearing. To help the majority of cochlear implant users who do not have any functional residual acoustic hearing, electro-tactile stimulation (ETS) may be used because tactile sensation has a frequency range and perceptual capabilities similar to that produced by acoustic stimulation in the EAS users.MethodsFollowing up the first ETS study showing enhanced English sentence recognition in noise,1 the present study evaluated the effect of ETS on Mandarin tone recognition in noise in two groups of adult Mandarin-speaking individuals. The first group included 11 normal-hearing individuals who listened to a 4-channel, noise-vocoded, cochlear-implant simulation. The second group included 1 unilateral cochlear-implant user and 2 bilateral users with each of their devices being tested independently. Both groups participated in a 4-alternative, forced-choice task, in which they had to identify a tone that was presented in noise at a 0-dB signal-to-noise ratio via electric stimulation (actual or simulated cochlear implants), tactile stimulation or the combined ETS.ResultsWhile electric or tactile stimulation alone produced similar tone recognition (∼40% correct), the ETS enhanced the cochlear-implant tone recognition by 17-18 percentage points. The size of the present ETS enhancement effect was similar to that of the previously reported EAS effect on Mandarin tone recognition. Psychophysical analysis on tactile sensation showed an important role of frequency discrimination in the ETS enhancement.ConclusionTactile stimulation can potentially enhance Mandarin tone recognition in cochlear-implant users who do not have usable residual acoustic hearing. To optimize this potential, high fundamental frequencies need to be transposed to a 100-200 Hz range.

Here I identify two gaps in cochlear implants that have been limiting their performance and acceptance. First, cochlear implant performance has remained largely unchanged, despite the number of publications tripling per decade in the last 30 years. Little has been done so far to address a fundamental limitation in the electrode-to-neuron interface, with the electrode size being a thousand times larger than the neuron diameter while the number of electrodes being a thousand times less. Both the small number and the large size of electrodes produce broad spatial activation and poor frequency resolution that limit current cochlear implant performance. Second, a similarly rapid growth in cochlear implant volume has not produced an expected decrease in unit price in the same period. The high cost contributes to low market penetration rate, which is about 20% in developed countries and less than 1% in developing countries. I will discuss changes needed in both research strategy and business practice to close the gap between prosthetic and normal hearing as well as that between haves and have-nots.

For cochlear implant users, combined electro-acoustic stimulation (EAS) significantly improves the performance. However, there are many more users who do not have any functional residual acoustic hearing at low frequencies. Because tactile sensation also operates in the same low frequencies (

ObjectiveTo record envelope following responses (EFRs) to monaural amplitude-modulated broadband noise carriers in which amplitude modulation (AM) depth was slowly changed over time and to compare these objective electrophysiological measures to subjective behavioral thresholds in young normal hearing and older subjects.DesignParticipantsthree groups of subjects included a young normal-hearing group (YNH 18 to 28 years; pure-tone average = 5 dB HL), a first older group ("O1"; 41 to 62 years; pure-tone average = 19 dB HL), and a second older group ("O2"; 67 to 82 years; pure-tone average = 35 dB HL). Electrophysiology: In condition 1, the AM depth (41 Hz) of a white noise carrier, was continuously varied from 2% to 100% (5%/s). EFRs were analyzed as a function of the AM depth. In condition 2, auditory steady-state responses were recorded to fixed AM depths (100%, 75%, 50%, and 25%) at a rate of 41 Hz. Psychophysics: A 3 AFC (alternative forced choice) procedure was used to track the AM depth needed to detect AM at 41 Hz (AM detection). The minimum AM depth capable of eliciting a statistically detectable EFR was defined as the physiological AM detection threshold.ResultsAcross all ages, the fixed AM depth auditory steady-state response and swept AM EFR yielded similar response amplitudes. Statistically significant correlations (r = 0.48) were observed between behavioral and physiological AM detection thresholds. Older subjects had slightly higher (not significant) behavioral AM detection thresholds than younger subjects. AM detection thresholds did not correlate with age. All groups showed a sigmoidal EFR amplitude versus AM depth function but the shape of the function differed across groups. The O2 group reached EFR amplitude plateau levels at lower modulation depths than the normal-hearing group and had a narrower neural dynamic range. In the young normal-hearing group, the EFR phase did not differ with AM depth, whereas in the older group, EFR phase showed a consistent decrease with increasing AM depth. The degree of phase change (or phase slope) was significantly correlated to the pure-tone threshold at 4 kHz.ConclusionsEFRs can be recorded using either the swept modulation depth or the discrete AM depth techniques. Sweep recordings may provide additional valuable information at suprathreshold intensities including the plateau level, slope, and dynamic range. Older subjects had a reduced neural dynamic range compared with younger subjects suggesting that aging affects the ability of the auditory system to encode subtle differences in the depth of AM. The phase-slope differences are likely related to differences in low and high-frequency contributions to EFR. The behavioral-physiological AM depth threshold relationship was significant but likely too weak to be clinically useful in the present individual subjects who did not suffer from apparent temporal processing deficits.

ConclusionThis study described objective and subjective evaluations of the Nurotron® Venus™ Cochlear Implant System and indicated that this system produced a satisfactory performance.ObjectiveTo observe the performance of the Nurotron® Venus™ cochlear implant (CI) system via electrophysiological and psychophysical evaluations.MethodsA 26-electrode CI system was specially designed. The performance of MRI in animal and cadaveric head experiments, EABR in cats experiment, the correlation between ESRT and C level, and psychophysics evaluations in clinical trials were observed.ResultsIn the animal and cadaveric head experiments, magnet dislocation could not be prevented in the 1.5 T MRI without removal of the internal magnet. The EABR was clearly elicited in cat experiment. In the clinical trial, the ESRT was strongly correlated with C level (p

The effective and efficient treatment of diseases, such as HIV, cancer or hereditary diseases, requires accurate and precise control of the combinatorial drug-dosage and their release. Herein, we introduce a simple photosensitive poly(ethylene glycol) diacrylate (PEGDA) hydrogel based platform for high dynamic range testing of combinatorial cocktail drug screening using three chemical and two protein drug treatments for colon cancer. UV cross linked PEGDA hydrogel droplet arrays on a Teflon patterned glass substrate enable a rapid yet accurate selection and dosage assignment of the drugs. Precisely loaded cocktails of the anticancer drugs were simultaneously released in-parallel with the PEGDA hydrogel chips into 2D or 3D cultured HCT-8 colon cancer cells for combinatorial drug screening. We demonstrate the functionality of our UV gel-Drug Chips 1000 fold range of concentrations for each of the five drugs in 30 seconds to find the optimized drug cocktail using a fractional factorial control system. Our device has low drug consumption, requiring only 12 nL per screening run per droplet. In addition, our UV gel-Drug Chips were employed for find the optimized drug cocktail using a fractional search algorithm. Our cocktail drug response results for both 2D (cell viability is 7.3%) and 3D (cell viability is 10.8%) colon cancer cells were analogous to those found by conventional method (6.8 and 9.3 respectively). In contrast to conventional method, our approach is faster, more effective, less time consuming and requires a lower amounts of drug volume.

PURPOSE OF REVIEW: Electric stimulation is a potent means of neuromodulation that has been used to restore hearing and minimize tremor, but its application on tinnitus symptoms has been limited. We examine recent evidence to identify the knowledge gaps in the use of electric stimulation for tinnitus treatment. RECENT FINDINGS: Recent studies using electric stimulation to suppress tinnitus in humans are categorized according to their points of attacks. First, noninvasive, direct current stimulation uses an active electrode in the ear canal, tympanic membrane, or temporal scalp. Second, inner ear stimulation uses charge-balanced biphasic stimulation by placing an active electrode on the promontory or round window, or a cochlear implant array in the cochlea. Third, intraneural implants can provide targeted stimulation of specific sites along the auditory pathway. Although these studies demonstrated some success in tinnitus suppression, none established a link between tinnitus suppression efficacy and tinnitus-generating mechanisms. SUMMARY: Electric stimulation provides a unique opportunity to suppress tinnitus. Challenges include matching electric stimulation sites and patterns to tinnitus locus and type, meeting the oftentimes-contradictory demands between tinnitus suppression and other indications, such as speech understanding, and justifying the costs and risks of electric stimulation for tinnitus symptoms.

Long-term loudness perception of a sound has been presumed to depend on the spatial distribution of activated auditory nerve fibers as well as their temporal firing pattern. The relative contributions of those two factors were investigated by measuring loudness adaptation to sinusoidally amplitude-modulated 12-kHz tones. The tones had a total duration of 180 s and were either unmodulated or 100%-modulated at one of three frequencies (4, 20, or 100 Hz), and additionally varied in modulation depth from 0% to 100% at the 4-Hz frequency only. Every 30 s, normal-hearing subjects estimated the loudness of one of the stimuli played at 15 dB above threshold in random order. Without any amplitude modulation, the loudness of the unmodulated tone after 180 s was only 20% of the loudness at the onset of the stimulus. Amplitude modulation systematically reduced the amount of loudness adaptation, with the 100%-modulated stimuli, regardless of modulation frequency, maintaining on average 55%-80% of the loudness at onset after 180 s. Because the present low-frequency amplitude modulation produced minimal changes in long-term spectral cues affecting the spatial distribution of excitation produced by a 12-kHz pure tone, the present result indicates that neural synchronization is critical to maintaining loudness perception over time.

Although the cochlear implant has been widely acknowledged as the most successful neural prosthesis, only a fraction of hearing-impaired people who can potentially benefit from a cochlear implant have actually received one due to its limited awareness, accessibility, and affordability. To help overcome these limitations, a 26-electrode cochlear implant has been developed to receive China's Food and Drug Administration (CFDA) approval in 2011 and Conformité Européenne (CE) Marking in 2012. The present article describes design philosophy, system specification, and technical verification of the Nurotron device, which includes advanced digital signal processing and 4 current sources with multiple amplitude resolutions that not only are compatible with perceptual capability but also allow interleaved or simultaneous stimulation. The article also presents 3-year longitudinal evaluation data from 60 human subjects who have received the Nurotron device. The objective measures show that electrode impedance decreased within the first month of device use, but was stable until a slight increase at the end of two years. The subjective loudness measures show that electric stimulation threshold was stable while the maximal comfort level increased over the 3 years. Mandarin sentence recognition increased from the pre-surgical 0%-correct score to a plateau of about 80% correct with 6-month use of the device. Both indirect and direct comparisons indicate indistinguishable performance differences between the Nurotron system and other commercially available devices. The present 26-electrode cochlear implant has already helped to lower the price of cochlear implantation in China and will likely contribute to increased cochlear implant access and success in the rest of the world. This article is part of a Special Issue entitled .

Cochlear implant (CI) listeners have difficulty understanding speech in complex listening environments. This deficit is thought to be largely due to peripheral encoding problems arising from current spread, which results in wide peripheral filters. In normal hearing (NH) listeners, central processing contributes to segregation of speech from competing sounds. We tested the hypothesis that basic central processing abilities are retained in post-lingually deaf CI listeners, but processing is hampered by degraded input from the periphery. In eight CI listeners, we measured auditory nerve compound action potentials to characterize peripheral filters. Then, we measured psychophysical detection thresholds in the presence of multi-electrode maskers placed either inside (peripheral masking) or outside (central masking) the peripheral filter. This was intended to distinguish peripheral from central contributions to signal detection. Introduction of temporal asynchrony between the signal and masker improved signal detection in both peripheral and central masking conditions for all CI listeners. Randomly varying components of the masker created spectral-variance cues, which seemed to benefit only two out of eight CI listeners. Contrastingly, the spectral-variance cues improved signal detection in all five NH listeners who listened to our CI simulation. Together these results indicate that widened peripheral filters significantly hamper central processing of spectral-variance cues but not of temporal cues in post-lingually deaf CI listeners. As indicated by two CI listeners in our study, however, post-lingually deaf CI listeners may retain some central processing abilities similar to NH listeners.

Contemporary cochlear implants with multiple electrode stimulation can produce good speech perception but poor music perception. Hindered by the lack of a gold standard to quantify electric pitch, relatively little is known about the nature and extent of the electric pitch abnormalities and their impact on cochlear implant performance. Here we overcame this obstacle by comparing acoustic and electric pitch perception in 3 unilateral cochlear-implant subjects who had functionally usable acoustic hearing throughout the audiometric frequency range in the non-implant ear. First, to establish a baseline, we measured and found slightly impaired pure tone frequency discrimination and nearly perfect melody recognition in all 3 subjects acoustic ear. Second, using pure tones in the acoustic ear to match electric pitch induced by an intra-cochlear electrode, we found that the frequency-electrode function was not only 1-2 octaves lower, but also 2 times more compressed in frequency range than the normal cochlear frequency-place function. Third, we derived frequency difference limens in electric pitch and found that the equivalent electric frequency discrimination was 24 times worse than normal-hearing controls. These 3 abnormalities are likely a result of a combination of broad electric field, distant intra-cochlear electrode placement, and non-uniform spiral ganglion cell distribution and survival, all of which are inherent to the electrode-nerve interface in contemporary cochlear implants. Previous studies emphasized on the mean shape of the frequency-electrode function, but the present study indicates that the large variance of this function, reflecting poor electric pitch discriminability, is the main factor limiting contemporary cochlear implant performance.

Recent evidence suggests that late auditory evoked potentials (LAEP) provide a useful objective metric of performance in cochlear implant (CI) subjects. However, the CI produces a large electrical artifact that contaminates LAEP recordings and confounds their interpretation. Independent component analysis (ICA) has been used in combination with multi-channel recordings to effectively remove the artifact. The applicability of the ICA approach is limited when only single channel data are needed or available, as is often the case in both clinical and research settings. Here we developed a single-channel, high sample rate (125 kHz), and high bandwidth (0-100 kHz) acquisition system to reduce the CI stimulation artifact. We identified two different artifacts in the recording: 1) a high frequency artifact reflecting the stimulation pulse rate, and 2) a direct current (DC, or pedestal) artifact that showed a non-linear time varying relationship to pulse amplitude. This relationship was well described by a bivariate polynomial. The high frequency artifact was completely attenuated by a 35 Hz low-pass filter for all subjects (n = 22). The DC artifact could be caused by an impedance mismatch. For 27% of subjects tested, no DC artifact was observed when electrode impedances were balanced to within 1 kΩ. For the remaining 73% of subjects, the pulse amplitude was used to estimate and then attenuate the DC artifact. Where measurements of pulse amplitude were not available (as with standard low sample rate systems), the DC artifact could be estimated from the stimulus envelope. The present artifact removal approach allows accurate measurement of LAEPs from CI subjects from single channel recordings, increasing their feasibility and utility as an accessible objective measure of CI function.

Recent evidence suggests that late auditory evoked potentials (LAEP) provide a useful objective metric of performance in cochlear implant (CI) subjects. However, the CI produces a large electrical artifact that contaminates LAEP recordings and confounds their interpretation. Independent component analysis (ICA) has been used in combination with multi-channel recordings to effectively remove the artifact. The applicability of the ICA approach is limited when only single channel data are needed or available, as is often the case in both clinical and research settings. Here we developed a single-channel, high sample rate (125 kHz), and high bandwidth (0-100 kHz) acquisition system to reduce the CI stimulation artifact. We identified two different artifacts in the recording: 1) a high frequency artifact reflecting the stimulation pulse rate, and 2) a direct current (DC, or pedestal) artifact that showed a non-linear time varying relationship to pulse amplitude. This relationship was well described by a bivariate polynomial. The high frequency artifact was completely attenuated by a 35 Hz low-pass filter for all subjects (n = 22). The DC artifact could be caused by an impedance mismatch. For 27% of subjects tested, no DC artifact was observed when electrode impedances were balanced to within 1 kΩ. For the remaining 73% of subjects, the pulse amplitude was used to estimate and then attenuate the DC artifact. Where measurements of pulse amplitude were not available (as with standard low sample rate systems), the DC artifact could be estimated from the stimulus envelope. The present artifact removal approach allows accurate measurement of LAEPs from CI subjects from single channel recordings, increasing their feasibility and utility as an accessible objective measure of CI function.

Abnormal auditory adaptation is a standard clinical tool for diagnosing auditory nerve disorders due to acoustic neuromas. In the present study we investigated auditory adaptation in auditory neuropathy owing to disordered function of inner hair cell ribbon synapses (temperature-sensitive auditory neuropathy) or auditory nerve fibres. Subjects were tested when afebrile for (i) psychophysical loudness adaptation to comfortably-loud sustained tones; and (ii) physiological adaptation of auditory brainstem responses to clicks as a function of their position in brief 20-click stimulus trains (#1, 2, 3 … 20). Results were compared with normal hearing listeners and other forms of hearing impairment. Subjects with ribbon synapse disorder had abnormally increased magnitude of loudness adaptation to both low (250 Hz) and high (8000 Hz) frequency tones. Subjects with auditory nerve disorders had normal loudness adaptation to low frequency tones; all but one had abnormal adaptation to high frequency tones. Adaptation was both more rapid and of greater magnitude in ribbon synapse than in auditory nerve disorders. Auditory brainstem response measures of adaptation in ribbon synapse disorder showed Wave V to the first click in the train to be abnormal both in latency and amplitude, and these abnormalities increased in magnitude or Wave V was absent to subsequent clicks. In contrast, auditory brainstem responses in four of the five subjects with neural disorders were absent to every click in the train. The fifth subject had normal latency and abnormally reduced amplitude of Wave V to the first click and abnormal or absent responses to subsequent clicks. Thus, dysfunction of both synaptic transmission and auditory neural function can be associated with abnormal loudness adaptation and the magnitude of the adaptation is significantly greater with ribbon synapse than neural disorders.

Electric stimulation of the auditory nerve via a cochlear implant (CI) has been observed to suppress tinnitus, but parameters of an effective electric stimulus remain unexplored. Here we used CI research processors to systematically vary pulse rate, electrode place, and current amplitude of electric stimuli, and measure their effects on tinnitus loudness and stimulus loudness as a function of stimulus duration. Thirteen tinnitus subjects who used CIs were tested, with nine (70%) being "Responders" who achieved greater than 30% tinnitus loudness reduction in response to at least one stimulation condition and the remaining four (30%) being "Non-Responders" who had less than 30% tinnitus loudness reduction in response to any stimulus condition tested. Despite large individual variability, several interesting observations were made between stimulation parameters, tinnitus characteristics, and tinnitus suppression. If a subject's tinnitus was suppressed by one stimulus, then it was more likely to be suppressed by another stimulus. If the tinnitus contained a "pulsating" component, then it would be more likely suppressed by a given combination of stimulus parameters than tinnitus without these components. There was also a disassociation between the subjects' clinical speech processor and our research processor in terms of their effectiveness in tinnitus suppression. Finally, an interesting dichotomy was observed between loudness adaptation to electric stimuli and their effects on tinnitus loudness, with the Responders exhibiting higher degrees of loudness adaptation than the Non-Responders. Although the mechanisms underlying these observations remain to be resolved, their clinical implications are clear. When using a CI to manage tinnitus, the clinical processor that is optimized for speech perception needs to be customized for optimal tinnitus suppression.

Tinnitus is a phantom sensation of sound in the absence of external stimulation. However, external stimulation, particularly electric stimulation via a cochlear implant, has been shown to suppress tinnitus. Different from traditional methods of delivering speech sounds or high-rate (>2000 Hz) stimulation, the present study found a unique unilaterally-deafened cochlear implant subject whose tinnitus was completely suppressed by a low-rate (