Jinsheng Zhang - US grants

DESCRIPTION (provided by applicant): Tinnitus is a phantom sound that occurs in the absence of external stimulation. It can have debilitating effects on millions of patients, creating a significant economic impact on our society. Among numerous management strategies being sought, auditory cortex electrical stimulation (ACES) has recently been used clinically to suppress tinnitus. This treatment has yielded promising results and has the potential of becoming an important approach in managing tinnitus. However, large variability in the efficacy of ACES-induced tinnitus suppression across individuals has hindered its development into a reliable therapy. The goal of this project is to develop an ACES rat model of tinnitus suppression. In Aim 1, we will test the hypothesis that ACES suppresses noised-induced tinnitus in rats. To test this hypothesis, we will implant chronic electrode arrays in the rat auditory cortex (AC). Following recovery from surgery, baseline behavioral data before noise exposure will be evaluated for tinnitus using a gap detection startle reflex paradigm. To induce tinnitus, each animal will be exposed to a 16 kHz octave band noise delivered at 124-130 dB SPL for 15 minutes or 2 hours. Upon confirming the presence of tinnitus, electrical stimulation of the AC will be performed. Behavioral testing for tinnitus will again be performed after ACES to determine its suppressive effects on the behavioral evidence of tinnitus. Before and after tinnitus induction with noise exposure, hearing thresholds will be measured by the pre-pulse inhibition startle reflex and the acoustically evoked auditory brainstem responses. The data will be used to separate tinnitus positive animals without hearing loss from those with hearing loss. In Aim 2, we will optimize stimulation strategies of ACES to suppress noise-induced tinnitus. We will conduct comparative studies to determine where and how to stimulate in order to obtain maximum suppression of tinnitus. The comparisons will be made between stimulation of the ipsilateral and contralateral AC to a manipulated ear, auditory core and belt regions, and epidural and intra-parenchymal (intracortical) tissues. In addition, we will examine the suppressive effects using different stimulation parameters such as single and train pulses, intensity, pulse rate, and duration. Developing this animal model is a crucial step for identifying optimal stimulation strategies - directly impacting clinically relevant issues. Establishing this model will also allow an in-depth investigation of the mechanisms that underlie ACES-induced tinnitus suppression. A clear understanding of these mechanisms will in turn facilitate the development of ACES as a reliable therapy. Finally, research in this direction will help gain more insights into the mechanisms of tinnitus. Tinnitus is a prevalent public health problem that affects millions of people and imposes a significant economic burden to society. Among numerous management strategies being sought, auditory cortex electrical stimulation (ACES) has become an important and promising approach in managing tinnitus. The goal of this project is to establish an animal model of ACES to suppress tinnitus. Developing this animal model will allow in-depth investigation of the mechanisms underlying ACES-induced tinnitus suppression, stimulate advanced clinical trials and facilitate development of ACES as a reliable therapy.

Abstract
Research objectives and approaches: The objective of this research is to develop next generation 3-dimensional (3D) neural probes with combined electrical and chemical interfaces. The approach of the proposed neural probe technology is based on a flexible skin technology and a simple folding process.

Intellectual merit: The proposed technology simplifies the fabrication and assembly process of high density 3D arrays of electrodes. Furthermore, this technology enables integration of microchannels with 3D neural probes. These channels, together with electrodes, enable combined electrical and chemical stimulation, thus opening the door to many important new applications. Local drug delivery at the implantation site by microchannels would be a promising approach to reduce/suppress tissue response, one of the major obstacles for successful chronic implantation.

Broader impacts: The proposed neural probes are expected to make a significant impact on treatment of many neural disorders such as paralysis, refractory epilepsy, Parkinson?s disease, Alzheimer?s disease, blindness, deafness, and tinnitus. These probes will also help us to better understand the operation of the brain, as a result of the 3D spatial resolution and multi-modal stimulating/sensing capability. The new methods and findings will be incorporated into a Micro/Nano-Electro-Mechanical Systems course developed by Prof. Xu. A unique component of the education plan is the training of an MD/Ph.D student. This team is committed to broaden the participation of underrepresented groups, evidenced by the PI?s active role in the Research Apprentice Program for Minority Students in Detroit Public Schools.

DESCRIPTION (provided by applicant): Numerous treatment modalities for tinnitus have been attempted, including drugs, noise-masking, Tinnitus Retraining Therapy, Neuromonics, and electrical stimulation. Cochlear electrical stimulation (CES) via cochlear implants is a frequently studied approach due to its promising results in managing patients' tinnitus. Cochlear implants and their speech processors are mainly designed for hearing restoration, however, CES has not been specifically designed and used to manage tinnitus. In addition, the underlying mechanisms of CES-induced tinnitus suppression remain unclear. In this project, we propose to develop a rat model of CES-induced tinnitus suppression using new thin-film based cochlear implant devices and to investigate the underlying neural mechanisms of the induced tinnitus suppression. Specifically, in Aim 1, we will test whether CES suppresses behavioral evidence of tinnitus in rats and whether CES induces more robust tinnitus suppression than auditory cortex or cochlear nucleus stimulation. In addition, we will test different parameters such as stimulation locations (apical vs. basal stimulation), patterns (single pulse vs. pulse train stimulation), duration, rate and intensity in order to identify optimal stimulation strategies. In Aim 2, we will elucidate the underlying mechanisms of CES-induced tinnitus suppression by investigating its induced changes in neural correlates of tinnitus in the rat auditory cortex. Specifically, we will determin whether CES-induced tinnitus suppression results from down-regulation of tinnitus-related hyperactivity, neurosynchrony, bursting, and tonotopic reorganization in the auditory cortex. Developing this animal model will enable extensive testing of stimulation parameters to identify optimal strategies for tinnitus suppression, and will determine whether peripheral modulation is more effective than central modulation and whether bottom-up modulation is more robust than top-down modulation. Elucidation of the mechanisms underlying CES-induced tinnitus suppression will provide information to help improve clinical trials and tinnitus management. Our novel thin-film-based cochlear implants will help us to develop new and effective devices optimized for tinnitus suppression.