Hubert H. Lim, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): This research is focused on assessing the inferior colliculus central nucleus (ICC) to primary auditory cortex (A1) neural projection using electrical stimulation (ES) of the ICC in a guinea pig model, in light of the development of a midbrain auditory prosthesis (MAP). Due to limitations of current auditory prostheses and the potential for improvements in frequency and level discrimination by ES of the ICC, experiments to determine the feasibility for a MAP are of interest. Therefore, it is important to study how the central auditory system organizes and processes sound information to assess how we might implement a MAP to achieve intelligible speech perception. A point-to-point tonotopic projection from the ICC to A1 has been shown. Thus, multi-channel electrodes will be used to electrically stimulate different ICC regions and simultaneously record neural activity across A1 to determine: (1) if segregated, parallel pathways from the ICC to A1 exist along the isofrequency dimension; and (2) if the temporal activation pattern along an isofrequency contour of A1 changes in response to ES of different regions within an isofrequency lamina of the ICC. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The brain is no longer viewed as a fixed system but a plastic system that adapts itself to optimally code for relevant stimuli. In some cases, the brain can experience abnormal plasticity. Hearing loss and tinnitus are two examples of debilitating conditions that affect millions of Americans and have been linked to abnormal tonotopic reorganization within the central auditory system. Understanding how tonotopic plasticity occurs within the auditory system and how we can acoustically and/or electrically stimulate the brain to induce appropriate changes in frequency coding to improve hearing can have significant clinical implications. Thus the long-term objective of the proposed studies is to map out the functional circuitry underlying tonotopic plasticity. Based on previous studies, plastic changes in frequency coding occur at all stages of the auditory pathway and involves both ascending and descending networks. However, the detailed functional organization between cortical and subcortical structures that can explain how tonotopic plasticity actually occurs within the central auditory system is still unknown. As an initial step towards identifying the detailed functional circuitry underlying tonotopic plasticity, the proposed studies will use various electrophysiological techniques to map out the functional and anatomical projection patterns from the primary auditory cortex (A1) to the central nucleus of the inferior colliculus (ICC). Both A1 and ICC have shown to play crucial roles in enabling central tonotopic reorganization. In particular, studies have demonstrated that best frequency (BF) shifts in A1 neurons induce similar BF shifts within subcortical structures, including ICC. Furthermore, BF shifts within ICC have also shown to contribute to BF shifts within A1. Using ketamine-anesthetized guinea pigs, the proposed studies will investigate how electrical stimulation of different frequency and isofrequency regions of A1 activate different frequency and isofrequency regions of ICC to begin to understand how A1 BF shifts induce similar shifts within ICC neurons. To identify the anatomical projection patterns, an innovative approach using antidromic stimulation will be used in which corticofugal neurons can be activated backwards from their axon terminals to their cell bodies. This method enables identification of mono- versus poly-synaptic projections from A1 throughout ICC. Thus in the same animal it is possible to map out the functional and anatomical projection pattern from A1 to ICC. Furthermore, BF shifts within ICC neurons will be induced using a conditioning paradigm (pure tone stimulation paired with stimulation of a BF matched A1 region). It is then possible to assess if and how the A1-to-ICC activation pattern altered as the acoustic-driven response patterns of ICC neurons change over time. These findings will begin to identify the functional circuitry underlying tonotopic plasticity that can guide future stimulation strategies for hearing loss and tinnitus. Furthermore, the developed electrophysiological methods can be expanded to investigate other brain regions of interest to the general neuroscience field. PUBLIC HEALTH RELEVANCE: In the U.S., approximately 36 million adults have reported hearing loss with about 40,000 receiving auditory implants and approximately 2 million people have reported debilitating tinnitus. Both tinnitus and poor speech perception with implants have been linked to abnormal frequency coding within the central auditory system. Thus the clinical goal of our proposed studies is to better understand how to acoustically and/or electrically activate the auditory system to improve frequency coding properties important for speech perception or tinnitus suppression.

DESCRIPTION (provided by applicant): The cochlear implant has achieved remarkable success in restoring hearing to deaf individuals through electrical stimulation of remaining nerve fibers near the cochlea. Unfortunately, cochlear implants are ineffective for those without a functional auditory nerve or implantable cochlea required for implementation. For these individuals, the only option is central auditory stimulation and the only FDA-approved device is the auditory brainstem implant (ABI), which is designed for stimulation of the cochlear nucleus. The ABI is mostly implanted in neurofibromatosis type 2 (NF2) patients who already have to undergo open head surgery to remove a tumor at the brainstem level and become deaf due to tumor-related damage of the auditory nerves. Although the ABI provides hearing improvements to these patients on a daily basis, it generally does not provide sufficient speech perception. One hypothesis is that the tumor removal process may damage brainstem structures crucial for speech understanding that can no longer be effectively activated with the ABI. To bypass this damaged region, a new auditory midbrain implant (AMI) was developed to stimulate in a higher structure, the inferior colliculus (IC). The IC has a well-defined tonotopic organization and is more surgically accessible than the cochlear nucleus, making it a favorable target for a new auditory implant. In a previous clinical trial, five NF2 patients were implanted with a single-shan array AMI device, which has shown to be safe and reliable for over six years. However, none of the patients have achieved sufficient speech understanding. Proceeding animal and human studies have identified the need for a new two-shank array that can more effectively activate across the three-dimensional IC structure. An improved surgical approach has also been developed for more consistently positioning the two-shank array into appropriate regions of the IC. The proposed project is a Phase I clinical study with the primary objective to demonstrate the safety and consistency of implantation and stimulation of this new two-shank AMI device in five NF2 patients at the leading auditory implant center in Germany. The secondary objective is to then show that this new implant can significantly improve hearing performance compared to the single-shank AMI and current ABI devices. To justify implantation of this new AMI device, only patients who have already been implanted with an ABI and achieve no or minimal benefit will be selected for this study. In other words, the AMI is their only hearing option. Each patient will be closely monitored across 8 to 10 testing sessions over a two year period to confirm the safety and reliability of the device over time. Various evaluations, speech tests, and psychophysical tests will also be performed to assess hearing performance with the AMI and to improve the stimulation strategies. Achieving the objectives of this study will justify proceeding Phase II/III trials and hopefully lead to commercialization of an improved central auditory prosthesis to benefit thousands of deaf patients worldwide.

ABSTRACT The proposed project will build and evaluate the safety and design needs of a new type of intracranial auditory prosthesis that targets the auditory nerve between the cochlea and the brainstem (auditory nerve implant, ANI) in order to substantially improve hearing performance over the current standard of care, the cochlear implant (CI). Current CIs provide crucial speech information to many recipients, but do not restore normal hearing, and are particularly challenged in noisy or complex acoustic environments. Despite concerted efforts over the past 25 years, little overall improvement in CI performance has been obtained, primarily due to the poor electrode- neural interface in which the CI electrodes are immersed in cochlear fluids and separated from the auditory nerve by the cochlea's bony wall. The new approach will build upon encouraging data from animal studies, well-established human surgical techniques to access the auditory nerve, and high-density electrode and safe stimulation technologies currently available for human use in order to test the safety and efficacy of the ANI that enables direct contact between the electrodes and the auditory nerve. The ANI provides great promise of improved speech and music perception for its prospective recipients, by overcoming the challenge that has limited improvements in CIs for the past quarter century. The first aim is to design and build a full ANI system in accordance with regulatory requirements, including necessary reliability, safety, functional, biocompatibility, and sterilization testing for human use. The ANI system will be built by combining a well-established CI device in the auditory implant field with a novel electrode and cabling technology already being evaluated in human patients for other clinical applications. The second aim is to refine the ANI surgery in human cadaver experiments and acutely during other relevant in vivo operations to consistently position and anchor the electrode array and cabling into the target region. The third aim is to develop and validate critical psychophysical tests to properly evaluate the performance of the ANI during the pilot human study, which can then inform the design of a future clinical ANI device. The fourth aim is to seek regulatory approvals and set up the clinical trial infrastructure and monitoring entities. The fifth and final aim is to perform a pilot ANI study in up to three deaf patients to obtain safety, reliability and functionality data that can properly guide the design of a proceeding clinical device and a feasibility study.

Project Summary The proposed ANI funded by the parent grant (1UG3NS107688-01) is a new central auditory prosthesis that targets the auditory nerve to substantially improve hearing performance (tonal range and resolution) over the current standard cochlear implant by interfacing directly with the auditory nerve. The funded parent grant supports the development and all necessary biocompatibility, safety and functional pre- clinical testing required to obtain an FDA Investigative Device Exemption (IDE) for the first in human demonstration in the UH3 part of the project. Since the start of the project in October 2018 it has become clear through discussions with the surgical team as part of the ongoing cadaver studies and a new FDA guidance on MRI compatibility for implantable devices, that a) having the ability to carry out an MRI in a human subject without the need to surgically remove the electrode would after all be highly desirable if not necessary, given the selected patient group(s) and b) that third party safety testing according to the new guidance is required to satisfy the need for highest possible safety for the study participants. These additional tasks were not anticipated or budgeted for in the original proposal. While the majority of regulatory, GMP and fabrication costs can be absorbed or are not affected by this additional task, the cost for the specific test devices and the third-party MRI testing provider would need to be added to the current budget through an administrative supplement. The third- party cost would be an overhead exempt pass through cost. The supplement project will evaluate potential safety hazards in patients with ANI devices for 1.5 and 3 T MRI systems through simulation and testing. This data will be provided to the FDA as part of the future IDE application and to BfArM for approval for use in the ANI clinical trial in Hannover, Germany. Based on a preliminary assessment, we anticipate that the generated data would support that the device can be considered conditionally MRI safe. If the full system is considered not MRI safe, then we can cut the cable and remove the stimulator module which only requires a superficial surgery and not the more invasive intracranial surgery to remove the electrode and assembly, assuming that the latter is passing the MRI safety testing. It will however stop the ability of patients to continue to participate in the study and to generate data. Only if the system and the electrode assembly are both considered MRI unsafe, would a full removal surgery be required. Beyond the specific need for this project, the supplement project will generate important safety, reliability and functionality data that can properly inform the design of a future clinical ANI devices and products at an early stage in the development cycle. The ability to allow MRI imaging in patients with chronic neuromodulation implants is seen as a critical potential barrier to widespread use.