John C. Middlebrooks - US grants

DESCRIPTION (provided by applicant): Normal spatial hearing is key to auditory scene analysis, which aids listeners in hearing out signals in the presence of competing sounds. Loss of this ability arguably is one of the greatest disabilities of people with mild-to-moderate hearin loss. We have characterized objective measures of scene analysis in human psychophysics and have examined some bottom-up mechanisms in auditory cortex in anesthetized cats. Now, we propose to examine the top-down cortical mechanisms of spatial aspects of auditory scene analysis, utilizing closely coordinated human and cat psychophysics with simultaneous cortical recordings in behaving cats. Specific Aim 1 addresses spatial stream segregation, by which listeners disentangle multiple interleaved sound sequences. In anesthetized conditions, cortical neurons exhibit the first steps of spatial stream segregation by synchronizing preferentially to one or the other of two competing sound sequences from differing source locations. Those anesthetized neurons, of course don't know which sequences correspond to target or to masker. Now, we will test the hypothesis that, during task performance with cortical recording, feline listeners select cortical modules synchronized to target sound sequences, either by facilitating modules synchronized to the target and/or by suppressing modules synchronized to the masker. Human and cat psychophysics and cat cortical physiology will evaluate spatial acuity in conditions in which listeners attend to spatial or to non-spatial segregation cues. Clinical reports and our recent results suggest that sound localization and spatial stream segregation are accomplished by different cortical areas. We will test this in humans by extending our observations that spatial segregation and localization differ markedly in their dependence on stimulus conditions. In cats, we will contrast spatial stream segregation among several candidate cortical areas. Aim 2 addresses spatial release from informational masking, which is the improvement in sound reception by spatial separation of a signal from a concurrent masker. Informational masking, in particular, is the masking that occurs in the absence of spectral overlap between signal and masker. In human and cat psychophysics, we will measure the trial-by-trial weights given to various masker components and will evaluate the degree to which various components and spatial cues contribute to spatial release. In cortical recordings from behaving cats, we will quantify masking of neural signal detection by out-of-band frequency components and the effects of spatial separation of signal and masker on rejection of such components. This work explores the monaural and binaural spatial cues for real-life auditory scene analysis. It will yield results that will inform design of sound processing strategies for hearing aids and cochlear implants. The new animal models that are introduced will yield new understanding of top-down task-dependent modulation of cortical spatial representation, enhancing diagnosis and treatment of spatial hearing deficits.

technology /technique development; animal tissue; prosthesis; nervous system; biomedical resource; biomedical equipment development; bioengineering /biomedical engineering; biomaterials; Mammalia;

Spatial hearing provides a powerful mechanism for discriminating sounds in noisy backgrounds. Project 1 will explore cortical mechanisms of spatial hearing, first in quiet, then in ambient noise. An audible sound must result in a time-varying distribution of activity across the cortex, which will be referred to here as the "cortical image" of that sound. To the extent that specific cortical images are unique to particular sounds, sound sources can be identified by their cortical images. This project will use multi-channel recording techniques to sample single-unit activity within cortical images at up to 32 sites simultaneously. In the context of this application, a cortical image may be regarded as the neuron-level correlate of the functional images that are observed with MRI, PET, and functional optical imaging, in this case with single-cell spatial and 1-ms temporal resolution. The goal of Specific Aim 1 is to identify the features of cortical images that can carry stimulus-related information. Artificial neural networks will be used to identify sound-source locations on the basis of cortical responses, and the accuracy of identification will reveal the relative amount of information that can be carried by particular elements of the responses of single neurons and of ensembles of up to 32 neurons. Particular study will be given to the relative amplitude and timing of activity among multiple units. Specific Aim 2 is designed in parallel with Project 2 to study spatial hearing in ambient noise. The degree to which specific elements of cortical responses track behavioral sensitivity to masker levels will reveal the relative significance of those features for signal detection and discrimination in ambient noise. The auditory cortex is a key element of the temporal lobe. The proposed project addresses the issue of how stimuli might be coded in the cerebral cortex by the coordinated activity of populations of neurons. The studies of the cortical image of a sound will complement diagnostic functional imaging techniques at the level of single neurons. This work should contribute to our understanding of the neural coding of perception, the evaluation of temporal lobe pathology and to the design of therapeutic responses to injury and disease.

This program explores the mechanisms that underlie the perception of complex sounds. Broad in its scope, its unifying theme is the problem of auditory processing in noise. There are three principal issues: 1) Spatial hearing in ambient noise. 2) Descending modulation of sound perception, considered from the level of efferent regulation of electromotility in the cochlea to animal behavior. 3) Stimulus-provoked cell death and protection of auditory structure and function by regenerative processes in the cochlea. The program is built on testable hypotheses and state-of-the-art methodology and is motivated by clear clinical insights. Six individual projects are based in the areas of cortical physiology, animal behavior, cochlear physiology, neuropharmacology, molecular genetics, and cochlear mechanics. The projects relate directly to deafness and to the treatment of deafness by investigating mechanisms of noise- induced acoustic trauma, novel approaches to evaluation of cochlear function, and feasibility of gene transfer in the cochlea. The proposed interdisciplinary approach and mutual interaction among the six projects is enhanced by three core resources. The morphology core provides for the necessary preparation and analysis of tissue from each of the six projects. The technical core will construct and maintain unique electrical and mechanical system components required by the individual projects. The administrative core supports all projects and cores. Although meritorious on their own, the six projects and three cores, taken as a whole, constitute a unique and integrated scientific endeavor. In summary, this program will provide significant new understanding of cortical mechanisms of complex signal processing, the processes underlying temporary and permanent hearing loss, the excitotoxic damage of cochlear nerve fibers, and a genetic therapy to rescue those damaged cells.

The most common application for which probes are requested is that of cortical recording. Although many different cortical areas are being explored (motor, visual, auditory), the preparations share similarities and problems which make collaborations with the Center and between external investigators increasingly important. Along with providing standard probes for acute cortical recording, the Center is working with collaborators (both institutional and corporate) to come up with probes, connectors, chamber designs and preparations for long-term implants. The challenges encountered in most of these preparations include placement of multiple devices into a single cranial chamber; maintaining positional stability of the probes; and inhibition of tissue encapsulation around the cable or 3-D platform due to healing of the cranium and dura. Several of the above collaborators continue to work on cranial chambers designed to hold several integrated cable/probes (either 2-D or 3-D) which protrude from the chamber edge into the cortical area. Some of the fixtures include a removable cap for access to the implants for inspection, cleaning and/or probe replacement. In the area of probe stability, collaborators are working with adhesives such as cyanoacrylate and fibrin glue to anchor the probes to the brain's surface. The University of Michigan Department of Materials Science and Engineering is also developing biological "glues" as well as materials which will inhibit tissue adhesion to apply to probe substrates. Surgical methods such as tenting of the dura over the probe insertions are being explored as well.

Clinical experience and psychophysical research indicate that the configuration of electrical currents on each channel of a cochlear prosthesis can have great impact on recognition of speech and other signals. The goal of this research program is to elucidate mechanisms relevant to normal and prosthetic hearing that can guide development of clinical stimulation strategies. The proposed experiments will compare the quality of stimulus representation in the auditory cortex determined by various cochlear current configurations. Monopolar and other configurations that are presumed to produce diffuse neural activation will be compared with bipolar and other configurations thought to produce more focal activation. Experiments will be conducted in guinea pigs. Specific Aim 1 is to characterize the distribution of unit activity across cortical location and post-stimulus time in response to stimulation of a single cochlear channel. Multi-channel cortical recording probes will permit simultaneous unit recording at 16 cortical sites. Artificial neural-network techniques will test the accuracy with which cochlear stimulation channels can be identified on the basis of patterns of cortical activity. Stimulus current levels will be expressed relative to psychophysical thresholds assessed in individual subjects. Specific Aim 2 will test interactions between cochlear channels, using single pulses and amplitude-modulated pulse trains. Cortical phase locking to stimulus modulation will be quantified, then the influence of a simultaneous or interleaved masking pulse train presented on a second cochlear channel will be assessed. Animal psychophysical experiments in Specific Aim 3 will measure thresholds for modulation detection in the presence and absence of a masker on a second cochlear channel. Stimulus conditions will be compared that, in the cortical experiments, either minimize or maximize interaction between cochlear channels. Specific Aim 4 is to identify current configurations that are particularly suited to various histories of deafness and stimulation. The results will be used to examine the central mechanisms that underlie effects of duration of deafness and stimulation. These results will be used to examine the central mechanisms that underlie effects of duration of deafness on prosthesis function.

The Technical Services Core comprises facilities and personnel for three units: a Computing Support Facility, an Electronic Instrument Lab and a Mechanical Instrument Lab. These units will assure the efficient operation of all scientific programs and will encourage new research initiatives through assistance with design, troubleshooting, maintenance, and product procurements. The Core Director, Dr. Middlebrooks, will serve as the faculty supervisor for this Technical Services Core. He will facilitate dialog between technical services personnel and investigators to introduce innovative technical solutions into research programs. The Computing Support Facility administers the Novell network used by the laboratories and research cores, conducts regular backup of research data, sets up new computer systems, oversees software acquisition and upgrades, and troubleshoots computer software and hardware. The Computing Consultant will help faculty keep abreast of new developments and will suggest and implement novel software and network applications, including setup of multi-user databases. The Computing Support Facility will coordinate with the Electronic Instrument Lab in implementation of custom hardware/software interfaces. The Electronic and Mechanical Instrument Labs will provide innovative design, fabrication, maintenance, and calibration of custom instruments. Personnel are experienced in project development, from the back-of-theenvelope conceptual stage through to installation and calibration. The Electronic Lab has expertise in analog and digital instrument design, with extensive experience in issues that are unique to auditory research. The Mechanical Lab is accomplished in design, fabrication, maintenance, and repair of micro- through largescale instruments. Use of common instrument laboratories will enhance exchange of results among laboratories and will provide economy of scale in production of certain broadly used instruments. The current facilities have proven indispensable in optimizing electronic, mechanical, and computing applications. The use of common technical services and the input of technical-core personnel into research design and methods has in the past fostered innovative research collaborations among KHRI investigators. In the proposed grant period, those services will be extended to a broader regional user base.

1. Project Summary. This project aims to improve hearing restoration for severely and profoundly deaf people. The present-day standard of care for restoration of hearing is a cochlear implant (CI), consisting of 16- 22 metal electrodes inserted into the scala tympani of the cochlea. Most CI users can expect to achieve reasonable speech reception in quiet environments. Performance is unsatisfactory, however, in everyday complex auditory scenes containing background noise and competing talkers, as in restaurants and in busy offices and classrooms. Also, CI users have only limited sensitivity to cycle-by-cycle temporal fine structure of sounds, which underlies temporal pitch perception. The impaired pitch perception exacerbates the problems of hearing in complex scenes, impairs voice recognition and sensitivity to the emotional content of speech, limits music appreciation, and degrades understanding of Mandarin and other tonal languages. We have shown in short-term studies in anesthetized cats that a penetrating intraneural (IN) electrode array inserted into the cochlear nerve can overcome many limitations of a CI. In particular, an IN electrode can selectively activate low-frequency cochlear and brainstem pathways that are specialized for transmission of temporal fine structure information. We now wish to translate IN stimulation to human trials. Specifically, we propose to test the feasibility of an implanted prosthesis; our working name for the device is ?CI+1?. The CI+1 consists of 15 channels of a 16-channel Advanced Bionics CI combined with a single-channel iridium electrode that will penetrate the cochlear nerve to target low-frequency cochlear nerve fibers. The iridium electrode is equivalent to one shank of the 8-10 shank penetrating auditory brainstem implant that has been used in FDA-approved clinical trials. Specific Aim 1 is to test the safety and efficacy of 6-month implantations of the CI+ 1 in cats, with daily stimulation. We will measure the electrically evoked auditory brainstem response (eABR) at 2-wk intervals to track any changes in stimulation threshold. Then, in a terminal experiment involving recordings along the tonotopic axis of the inferior colliculus, we will assess spread of excitation and transmission of temporal information by the intrascalar and IN electrodes. Specific Aim 2 is to evaluate short-term IN stimulation in human patients who are undergoing surgery to resect vestibular schwannomas. Specific Aim 3 is to evaluate optimal surgical approaches for CI+1 implantation using studies of cadaveric human temporal bones. Early in the 5th year of funding, we aim to have completed the necessary background studies and to apply for an investigational device exemption from the FDA that will permit translation of the CI+1 to the first human trials. We anticipate that the CI+1 will offer the first human volunteers essentially all the benefits of a conventional CI plus enhanced sensitivity to low-frequency sounds and enhanced pitch perception. In clinical applications, the CI+1 might initially be favored for certain applications, but in principle the device would be a preferred alternative for nearly every candidate for cochlear implantation.