Daniel J. Tollin, D.Phil. - US grants

Our sense of hearing is surely one of the most important senses particularly because it allows communication through speech. The auditory system can also determine the location from which sounds arrive. While speech can be understood reasonably well using only one ear, determination of the spatial location of sound requires both ears because the auditory receptors encode the frequencies of sounds, not their locations; central comparisons of neural signals evoked by the acoustic inputs to the two ears are required. The long-term goal is to understand the neural bases of sound localization. One objective of the proposed train is to acquire the methods, techniques, and skills necessary for studying the neural mechanisms for binaural hearing in the cat. The training is designed to build on the applicant's background in behavioral studies of binaural hearing in human observers. The training will encompass two specific aims, both of which investigate two structures though to be important for sound localization. Aim I investigates how the three main sound localization cues are encoded in the lateral superior olive (LSO) of the anesthetized cat using a Virtual Acoustic Space (VAS) technique. The VAS approach affords precise independent manipulation of the cues which is crucial to determining the coding strategies of the LSO. Aim II investigates the effects of echoes on sound localization and on the coding of location in the inferior colliculus (IC). Single units in the IC or an awake cat will be recorded from while the cat is actively participating in a psychophysical sound localization task. The ultimate goal of the training is to develop an integrative approach to understanding hearing which combines traditional behavioral and neurophysiological approaches. Such an integrated approach is required to relate behavioral processes to their neural substrates.

DESCRIPTION (provided by applicant): The goals of this project are to understand the concurrent development of the acoustical cues to sound source location and the neural circuits that encode them. All cues for localization can be captured in measurements of head related directional transfer functions (DTFs), which contain the three main cues, interaural differences in time (ITDs) and level (ILDs) and monaural spectral shape cues. Since the formation of these cues is governed by the linear dimensions of the head and pinnae, the relative magnitudes of the cues will change as these structures grow. These experiments test the hypothesis that during the development of one of the cues, ILD, there is a concomitant development of the ability of cells in the lateral superior olive (LSO), one of the most peripheral sites for binaural interaction, to encode ILDs. Aim I will test the hypothesis that the cues will change in ways predictable from the increasing dimensions of the head and pinnae. DTFs will be measured in kittens aged from 1 week to adult and the cues to location extracted from them. The cues will be compared to measurements of the head and pinnae. Aim II will test the hypothesis that the range of ILDs encoded by LSO cells will increase during development with the expected increase in the magnitudes of the physical ILDs, as measured in Aim I. Also, the ability of cells in the medial nucleus of the trapezoid body, which provide the contralateral inhibitory input to the LSO, to encode the complex spectral shapes necessary for ILD computation will be studied. These studies will determine if and how long these nuclei in the ascending binaural system can compensate for changes in the cues brought about by developmental changes in the acoustical properties of the head and pinnae. Finally, Aim III will study the normal mechanisms by which the cues to location, in particular those based on spectral shape (ILDs and monaural spectral cues), are encoded by the LSO and its afferents in adult cats. Several techniques, including virtual space stimulation and a systems identification method, will be used in Aims II and II1. We hypothesize that across a population of inputs to the LSO, complex spectral shape is represented and that the LSO computes a spectral difference to extract the ILD from these inputs. A better understanding of how complex sound spectra are represented will lead to better designs for the processing strategies in auditory prosthetics like cochlear implants and hearing aids.

PROJECT SUMMARY Binaural hearing allows accurate and precise localization of sounds, and also confers advantages in complex environments such as workplaces, classrooms, restaurants, etc. where competing speech streams, noisy backgrounds, and reverberation abound. Unfortunately, an increasing population, spanning infancy through elderly and of diverse etiology, experiences severe difficulty in such environments despite having normal audiometric thresholds. Such difficulties are a hallmark of Central Auditory Processing Disorder, CAPD, which refers to difficulties in processing acoustic information in the central auditory system as demonstrated by poor hearing performance, often specifically in binaural hearing tasks. CAPD-like challenges can emerge as a result of temporary conductive hearing loss, aging, traumatic brain injury, autism, neurodegenerative diseases (multiple sclerosis) and use of bilateral clinical devices (hearing aids, cochlear implants). The consequences of CAPD can be severe; in children, CAPD impacts speech and language learning and academic performance and in adults, quality of life, job performance, fitness for duty, social interactions, etc. Regardless of etiology, a major limitation in CAPD is that clinical diagnosis is based on a cluster of symptoms, many of which overlap with other developmental disorders such as attention deficit hyperactivity disorder, learning disabilities and language deficits. Moreover, behavioral assessments of auditory processing, particularly in children and elderly, have poor reliability with scores often reflecting higher-level cognitive or analytical processes rather than basic auditory sensory processing. Thus, early intervention and implementation of rehabilitation strategies in CAPD patients is precluded. A potential way to surmount this barrier is to use non-invasive electrophysiological measures. Auditory brainstem responses (ABRs) are used worldwide for newborn and adult hearing screening. Because different ABR waves broadly represent activity within different parts of the auditory pathway, it is possible to assess the functional state of distinct stages of the pathway using appropriate stimuli. Binaural stages can be assessed using the binaural interaction component (BIC) of the ABR. The BIC is the residual ABR obtained after subtracting the sum of monaurally- from binaurally-evoked ABRs. Prior research has identified the BIC as a potential biomarker for binaural ability. As the BIC can be measured using equipment and methods already available in most audiology clinics, its development as diagnostic tool could have immediate and widespread clinical value. However, while comparative studies have reported robust BIC in a variety of model species, reports of human BIC are perplexingly variable and unreliable. The proposed research comprises three Aims to establish a comprehensive understanding of the BIC, including 1) identification of its brainstem circuit origin, 2) identification of sources of variability across mammalian species including humans, 3) identification of best practices in human BIC measurement, and assessment of the BIC as a biomarker for predicting meaningful aspects of human binaural perception.

Project Summary One of the most common medical conditions in any aging society is presbycusis, or age-related hearing loss. Approximately one third of American adults suffer from this condition typically starting at middle age, and about half of adults over 70 years have a substantial hearing impairment. One of the mechanisms of presbycusis happens in the central nervous system and is termed central hearing loss. Older adults with central hearing loss may have normal or near normal audiograms yet have problems carrying on a conversation in complex environments, i.e. situations where multiple sound sources are active at the same time, such as a busy restaurant, a public place, or any situation where background noises are active. The main reason for this difficulty is that affected individuals have trouble perceptually isolating sound sources of interest (e.g., the voice of the speaker they want to listen to) effectively from other sources, presumably because the neural mechanisms that perform this computation are less effective. We propose a combined human subjects and animal model study to tackle this issue. Specifically, we propose to study the contribution of age-related changes in the sound localization pathway, located in the auditory brain stem, to this phenomenon. The overarching hypothesis of this proposal is that precise timing of neural activity within the sound localization pathway declines with age, leading to less precise binaural hearing and sound localization abilities. We hypothesize that these changes contribute to decreased behavioral performance in complex acoustic environments in both humans and animal models. For the human component, we will test the sound localization and hearing in noise abilities of ?young? and ?old? listeners, and relate decreased behavioral performance in older listeners to decreased temporal precision of neural activity in the sound localization pathway (aim 1). We will show that aged Mongolian gerbils recapitulate these age-related changes, making them good models to study this human condition (aim 2). We will then explore cellular mechanisms behind the decreased temporal precision of neural activity (aim 3). The expected results from this study will help determine the role of the sound localization pathway in this common medical condition, will help diagnose central hearing loss more objectively, will directly suggest mechanisms for the development of future medical interventions, and will help resolve a key challenge to healthy aging.

Project Summary We request in this proposal partial support to cover the expenses of the 9th International Meeting of the Middle Ear Mechanics in Research and Otology (MEMRO) 2021 conference, which will be held in June of 2021 at the University of Colorado's Boulder campus. Consistent with the goals of the first MEMRO meeting in 1996 the purpose of this triennial meeting is to bring together experts in middle ear science and engineering, with clinical otologists, in order to foster an exchange between these related but too often independent groups. Recent MEMRO meetings were held in Shanghai (2018) and Aalborg, Denmark (2015) and each attracted ~200 participants from over 20 countries. A goal of the 2021 meeting will be to continue to facilitate the free exchange of ideas between basic and clinical scientists, and to provide a framework for novel collaborative efforts in order to advance our clinical and scientific understanding of middle ear function, dysfunction and repair. The theme of the 2021 MEMRO meeting will be ?Advances in Middle Ear Science and OTO surgery?, highlighting our focus on the intersection between the two fields. An important goal of this meeting is to increase diversity in the attendees. In particular, we intend to specifically target otology residents and faculty by hosting a ?Middle-Ear Surgical Lab and Seminar? the day immediately prior to the formal MEMRO 2021 meeting. The 2021 MEMRO meeting is being organized by the University of Colorado School of Medicine and the meeting will be held on the nearby University of Colorado Boulder campus, chosen because of its convenient location allowing easy travel, idyllic campus and surroundings, and very reasonable costs with on- campus housing and dining options adjacent to the conference venue available for attendees.