Fan-Gang Zeng - US grants

Physiological studies have established that auditory neurons can be classified into two categories based upon their spontaneous rate (SR): low-SR neurons have higher thresholds and wider dynamic ranges than high-SR neurons. Our hypothesis is that high-SR neurons are primarily responsible for detection at threshold level whereas low-SR neurons are primarily responsible for suprathreshold discrimination tasks. The long-term objectives are to determine the contributions of high- and low-SR neurons to psychophysical performance in normal-hearing listeners and to differentiate possible functional deficits that hearing-impaired listeners may have due to the selective damage of the two groups of SR neurons. The specific aims are to assess the differential contributions of the two types of SR neurons to (1) intensity discrimination; (2) loudness sensation; (3) frequency discrimination; (4) pitch sensation; and (5) stop-consonant discrimination. The experimental design is based upon Relkin and Doucet's (1991) finding that low-SR neurons have a much slower recovery (2000 msec) from forward masking than high-SR neurons (100-200 msec). At signal delays of 100-200 msec, high-SR neurons are recovered from forward making while low-SR neurons are not. Thus, psychophysical measurements at a signal delay of 100-200 msec following a forward masker can differentiate the contribution of high- and low-SR neurons. The methods to be used are two- interval forced-choice adaptive procedure in experiments described in specific aims (1)-(4), and single-interval constant stimuli procedure in stop-consonant discrimination experiment (specific aim 5). Testing hypothesis put forth in this proposal could lead to better understanding the treatment of the speech recognition deficits in hearing- impaired listeners.

biomedical equipment purchase;

The long-term objectives of the proposed study are to (1) develop a unified theory of the encoding of sound intensity in normal-hearing, hearing-impaired, and implant listeners, (2) differentiate the functional deficits that hearing-impaired and implant listeners may have due to the delivery of altered peripheral excitation patterns the brain, and (3) design rehabilitative devices that can maximally compensate for the functional deficits in these listeners with hearing impairment. This proposal addresses the dynamic range problem for the encoding of intensity in both acoustic and electric hearing. On one hand, the acoustic dynamic range problem refers to the discrepancy between the large psychophysical loudness range and the limited physiological range demonstrated by the majority of individual auditory neurons. On the other hand, the electric dynamic range problem is a practical and harsh reality facing clinicians in fitting speech processors: implant listeners who have typically 6-20 dB range must accommodate normal speech and environmental sounds containing important information over a 40-60 dB range. The specific aims are to (1) understand the underlying neural mechanisms of encoding the enormous dynamic range in acoustic hearing, (2) quantify loudness growth and discrimination functions in electric hearing, and (3) determine which normal mechanisms are missing in electric hearing and whether it is possible to increase the electric dynamic range by compensating for these missing normal mechanisms. Our hypothesis is that loudness growth and discrimination functions are primarily determined by the peripheral excitation pattern and the central system responds in a similar fashion regardless of the changes in the peripheral inputs. Our experimental design is to measure loudness growth and discrimination functions in conditions that alter the peripheral inputs to the central system. Methods used to alter the peripheral inputs include acoustic high-pass noise, low- and band-pass noise, forward masking, amplitude or phase- modulated stimuli, vestibular-nerve-section, electric stimulation of the auditory nerve and cochlear nucleus. Corresponding physiological mechanisms to be examined are: spread of excitation along the basilar membrane, suppressive and excitatory masking, adaptation and low- spontaneous rate auditory neurons, synchronization of neural firing, contributions of efferent neurons, nonlinear vibration of the basilar membrane and its associated phenomena (e.g. lateral suppression). A unique feature of this proposal is that it uses cochlear implant, auditory brainstem implant, and vestibular neurectomy patients to better understand the neural mechanisms of encoding the large dynamic range of sound intensity. The results obtained from this proposal could lead to better designs of auditory prostheses and hearing aids that will compensate for the reduced dynamic range that occurs with both electric stimulation of the auditory system and hearing loss.

[unreadable] DESCRIPTION (provided by applicant): Cochleae implants have restored partial hearing to more than 100,000 hearing-impaired people worldwide. As cochlear implant performance continues to improve, more and more patients with residual acoustic hearing are eligible for, and some have received, a cochlear implant. We have identified three groups of implant patients who possess significant residual acoustic hearing: those who have a hearing aid on the contralateral side, those who use combined electro-acoustic stimulation in the same ear, and those who use the implant to suppress tinnitus and may have normal hearing contralaterally. We propose to systematically study the interactions between acoustic and electric hearing in these subjects. Our three specific aims are: 1. To construct an accurate pitch map in electric hearing 2. To measure psychophysical interactions between acoustic and electric stimulation 3. To probe the mechanisms and optimize the performance of bimodal hearing An accurate pitch map will allow us to reconstruct "electric harmonics" and develop authentic acoustic simulations of the cochlear implant. A systematic characterization of the psychophysical interactions is necessary to understand the mechanisms and maximize the benefit of bimodal hearing. The proposed work is of high clinical relevance because it may help overcome two of the most significant shortcomings of the current cochlear implants, namely, music perception and speech recognition with background noise, particularly when the noise is a competing voice. [unreadable] [unreadable] [unreadable]

As the only medical device that can restore hearing in deaf people, the cochlear implant has produced good speech recognition in quiet. However, the current implants are seriously limited in speech recognition in noise and in music perception. The long-term objectives of this research program are to understand signal processing in the normal auditory system and to restore functional hearing via auditory prostheses in hearing-impaired persons. Recent work from our laboratory and others has shown that pitch, temporal fine structure, and dynamic acoustic cues are crucial to improve realistic listening performance, but are not adequately encoded in current cochlear implants. Our working hypothesis is that extraction and encoding of these important cues will lead to an overall improvement in cochlear implant performance. We propose three novel methods to test this hypothesis. The three Specific Aims address each of these novel methods: (1) Co- vary stimulation rate and position to encode pitch;(2) Adapt modern vocoder algorithms to encode temporal fine structure;and (3) Use biologically-inspired signal processing to encode dynamic acoustic cues. Our multidisciplinary approach integrates psychophysical, speech coding, and signal processing techniques. A unique feature of this approach is that all algorithms are developed based on rigorous psychophysical and simulation measures, and will be evaluated and perfected in actual implant users with real-time implementations. Successful completion of the proposed research should yield results of high theoretical and practical significance. It will likely advance scientific knowledge on the centuries-old but still unresolved pitch coding question (Aim 1), bridge the technological gap between relatively rudimentary cochlear implants and modern telecommunication (Aim 2), and inspire translational work from basic research to clinical problems (Aim 3).

Our primary goal is to provide centralized and high-quality support for both basic and customized computing and engineering Service and training that can not only increase collaboration, efficiency and quality of existing research, but also stimulate new research in NIDCD mission areas at the University of California Irvine (UCI) and beyond. Our overall research strategy is to build upon and expand the service and support in computing arid engineering, according to the requests of the past, current and future core users with diverse backgrounds and needs. We have identified several common threads and developed signal processing tools, customized sound control, and formalized training to address these diverse backgrounds and needs. The present renewal application seeks to achieve the following three specific alms. Aim 1 will provide signal processing the popular support for core users in stimulus generation and data processing. Aim 2 will provide customized support for core users in sound control and prototype development. A highlight in Aim is collaboration with the Imaging core to build and integrate an ABR recording capability to be housed in the two-photo imaging facility. Aim 3 will provide network and education support for core users and the hearing research community.

Principal Investigator/Program Director (Last, first, middle): Zeng, Fan-Gang Tinnitus is the perception of sound in the absence of external sound. Tinnitus is a significant public health problem that affects 50 million Americans. Severe tinnitus disrupts daily functions from sleep to work, often leading to anxiety, depression and lowered quality of life. Despite significant advances in research and development, presently there is no cure for tinnitus. The present application uses noninvasive electric stimulation in the ear and minimally-invasive electric stimulation to the round window or promontory for safe and effective treatment of tinnitus. One innovation is to evaluate stimulation sites and patterns that evoke auditory sensations while minimizing non-auditory sensations. Another innovation is to provide two novel tinnitus treatment options, especially for those who still have significant acoustic hearing and cite tinnitus, and not hearing loss, as the main indication. In the preliminary study, 10 minutes of round window stimulation completely silenced the tinnitus not only during stimulation but also for 5 hours after the stimulation in a subject who had suffered from tinnitus for 15 years. Successful completion of the present work can lead to safe and effective medical devices for tinnitus treatment. Project Summary

Age-related decline in central auditory function significantly affects quality of life in the elderly, with impaired speech perception leading to increased risk for depression, social isolation and cognitive decline. A 2017 Lancet Commission report cites hearing loss as the largest modifiable risk factor for developing cognitive decline, exceeding smoking, high blood pressure, lack of exercise and social isolation. Remarkably, a 2019 large-scale study found that even mild hearing loss, i.e., still within the normal range, produced an even closer association with cognitive decline. Currently, there is no effective therapy for age-related central auditory decline?hearing aids only address audibility?and no drug treatment. Ideally, a combination of drug treatment with hearing aids and behavioral training could restore auditory function, but the development of pharmacological treatments requires a better understanding of the mechanisms by which candidate drugs improve hearing. The goals of this proposal are to develop biomarkers of altered auditory processing in aging mice and humans, and using these biomarkers, to test the hypothesis that nicotine can normalize these age-related central auditory deficits. Because nicotine enhances cortical and cognitive function, pharmaceutical companies are developing nicotine-like drugs to target cognitive deficits in aging. These drugs are non-addictive (unlike nicotine in tobacco), yet nicotine also is non-addictive when given topically or orally. However, its clinical benefits have not been exploited except as an aid to stop smoking. We hypothesize that: 1) acute nicotine compensates for the age-related decline in inhibition by exciting the remaining inhibitory neurons; 2) chronic nicotine exposure (CNE) upregulates nicotinic acetylcholine receptors (nAChRs); and, as a result, 3) acute nicotine and/or CNE will reduce or reverse the age-related auditory decline. We will test these hypotheses in both mouse and human at the level of cells (mouse in vitro brain slice), neural systems (mouse in vivo physiology; human brain imaging and EEG) and behavior (human psychoacoustics). Aim 1 will determine in mouse whether age-related decline in auditory spectrotemporal processing is reversed by acute nicotine or CNE, and characterize the associated cellular mechanisms. Aim 2 will identify, in humans, age-related changes in receptive field properties in auditory cortex using novel fMRI techniques and determine if nicotine reverses these changes using psychoacoustics, fMRI and EEG. This project features a multifaceted, parallel approach in mouse and human. Each Aim will: 1) examine auditory processing at multiple adult ages; 2) use similar acoustic stimuli in both species, accounting for species differences in hearing, to target common mechanisms; 3) test the effects of nicotine. A successful outcome will promote an integrated understanding across levels, from cellular mechanisms to perception, and facilitate translation of nicotine-based therapeutic treatments to clinical populations.