Oregon Health & Science University

Drug-mediated cochlear synapse regeneration: reversing central gain and hyperacusis in a gerbil model

Loud noise exposure in the workplace and everyday environments is one of the leading causes of hidden inner ear damage. While traditional hearing tests measure the quietest sounds a person can detect, they frequently miss a critical form of injury: the damage to the nerve connections (synapses) that carry sound signals from the inner ear to the brain. Because standard hearing tests only evaluate basic sound detection, individuals with this nerve loss can still register “normal” hearing thresholds on standard audiograms. However, behind this apparent typical hearing, the brain is not receiving normal auditory information from the ear.

To compensate for this reduced input, the central auditory system turns up its internal “volume knob.” This adaptive brain response, known as “central gain,” is an attempt to amplify faint signals. Unfortunately, when the volume remains turned up too high, it can cause decreased sound tolerance where some sounds become uncomfortably loud. Decreased sound tolerance can impact daily function and affects up to 15 percent of older adults, yet there are currently no approved medications available to repair auditory nerve damage.

To address this critical therapeutic gap, this project evaluates a promising strategy: repurposing an extensively tested, FDA-approved drug. Utilizing a medication with an already established human safety profile dramatically accelerates the timeline for bringing a tangible treatment to patients. This specific drug acts on key biological pathways that actively stimulate the repair and regeneration of damaged auditory nerve connections.

Our research will test two clinically practical delivery routes to determine the most effective approach: an oral pill that works systemically, and a targeted gel placed directly into the ear to deliver the medication locally. Using preclinical models of noise-induced damage, we will examine the direct relationship between rebuilding ear-to-brain nerve connections, turning down central gain in the brain, and restoring normal loudness perception.

Oregon Health & Science University
Neural mechanisms of hyperacusis in the inferior colliculus and cortex of ferrets with noise-induced auditory neurodegeneration

The development of effective treatments for hyperacusis (the diminished tolerance of loud sounds) and tinnitus (a persistent ringing in the ears) is limited by existing animal models. Current animal models are generated by high-intensity noise exposure or by the administration of salicylate, the active ingredient in aspirin. In addition to producing symptoms of hyperacusis and tinnitus, both of these manipulations lead to elevated hearing thresholds by damaging inner ear sensory cells. Damage to inner ear sensory cells leads to altered auditory processing, which makes it difficult to identify the specific changes that produce hyperacusis and tinnitus. While hearing loss is the primary risk factor for these disorders, they cannot be explained by damage to sensory cells alone. In fact, hyperacusis, tinnitus, and difficulty understanding speech in noise have been reported even in individuals with normal auditory thresholds. Therefore, in order to tease out the specific changes to the auditory system that result in tinnitus and hyperacusis, the ideal animal model should not have sensory cell damage.

Recent evidence from studies in mice suggests that moderate noise exposure can cause damage to the auditory nerve without altering hearing thresholds. Mice with this type of auditory nerve damage show symptoms of hyperacusis and humans who report tinnitus, but have normal auditory thresholds, also show signs of similar damage. It has also been hypothesized that auditory nerve damage will lead to increased difficulty understanding speech in the presence of background noise. Thus, moderate noise exposure provides a potential animal model for patients who have normal hearing thresholds, yet still experience hyperacusis, tinnitus, or difficulty hearing in noise. We will assess the perceptual effects of this auditory nerve damage by training noise-exposed ferrets to perform behavioral tests designed to parallel tests of hyperacusis, tinnitus, and difficulty hearing in noise that are conventionally used in human listeners. We will also assess how auditory responses in the central auditory system are altered by this type of auditory deficit to determine whether the changes in neural responses may explain the perceptual effects of hyperacusis, tinnitus, and difficulty hearing in noise.

Mass Eye and Ear, Harvard Medical School
Hyperacusis caused by abnormalities in auditory mechanics

Many hyperacusis patients have what is called “conductive hyperacusis,” due to mechanical abnormalities of the ear that result in a hypersensitivity to sounds/vibrations transmitted through their bodies. These include the sensation of one’s own voice (autophony), pulse, and body movements such as eye motion and footsteps, as well as sensing the vibrations of items such as vehicles. These symptoms are common among patients who have an opening in the bone encapsulating the inner ear (termed a superior canal dehiscence, a type of pathological third-window lesion).

Compared with hyperacusis stemming from neurosensory issues, conductive hyperacusis has the potential for treatment. Recently, surgical treatment for hyperacusis by changing the mechanics of surrounding structures of the inner ear show mixed results, with some patients experiencing worse symptoms after surgery.

Although these “experimental” surgical treatments in patients are increasing, the mechanisms of conductive hyperacusis are not well understood, and scientific research targeting this problem is lacking. This study aims to understand how mechanical changes in fresh cadaveric specimens with similar gross mechanics as the living can influence the cochlear input drive (an estimate of hearing), resulting in hyperacusis. Our novel intracochlear pressure measurement technique will allow the monitoring of the cochlear input drive as we manipulate the mechanics surrounding the inner ear.

University at Buffalo
Behavioral Model of Loudness Intolerance

High-level noise causes discomfort for typical-hearing individuals. However, following cochlear damage, even moderate-level noise can become intolerable and painful, a condition known as hyperacusis.

One of the critical requirements for understanding and finding a cure for hyperacusis is the development of animal models. I have developed two new animal behavior models to study the pain and annoyance components of hyperacusis. The Active Sound Avoidance Paradigm (ASAP) uses a mouse’s innate aversion to a light open area and preference for a dark enclosed box. In the presence of intense noise, the animal shifts its preference to the light area. The Auditory Nociception Test (ANT) is based on a traditional pain threshold assessment. Although animals show an elevated pain threshold in the presence of 90 and 100 dB, at 110 and 115 dB they show a reduced pain tolerance. Using these two tests together will allow me to assess emotional reactions to sound as well as the neural interactions between auditory perception and pain sensation.

University of Connecticut Health Center
Creation and validation of a novel, genetically induced animal model for hyperacusis

Hyperacusis is a condition in which a person experiences pain at much lower sound levels than listeners with typical hearing. While the presence of outer hair cell afferent neurons is known, it is not known what information the outer hair cells communicate to the brain through these afferents. This project’s hypothesis is that the function of these mysterious afferents is to communicate to the brain when sounds are intense enough to be painful and/or damaging, and that this circuitry is distinct from the cochlea-to-brain circuitry that provides general hearing. The hypothesis will be tested using a novel animal model in which a certain protein that is essential for the proposed “pain” circuit is missing. The absence of this protein is predicted to cause a lessening of the perception of auditory pain when high intensity sounds are presented. If true, this research has implications for those suffering from hyperacusis.

State University of New York at Buffalo
Noise-induced hyperacusis in rats with and without hearing loss

Hyperacusis is an auditory perceptual disorder in which everyday sounds are perceived as uncomfortably or excruciatingly loud. Researchers and audiologists assess hyperacusis in the clinic by asking patients to rate sounds based on their perceived loudness, resulting in a measure known as a loudness discomfort level (LDL). Loudness discomfort ratings are a useful clinical tool, but in the lab we cannot ask animals to “rate” sounds. Instead, to measure loudness perception in animals, our lab trains rats to detect a variety of sounds of varying intensity. By measuring how quickly the animals respond to each sound—faster in reaction to higher intensity sounds and more slowly to lower intensity sounds—we can obtain an accurate picture of perceived loudness in animals. By comparing electrophysiological recordings with behavioral performances of the individual animals, this project aims to characterize the relationship between changes in neural activity and loudness perception in animals with and without noise-induced hearing loss.

The relationship between pain-associated proteins in the auditory pathway and hyperacusis

Hyperacusis is a condition in which sounds of moderate intensity are perceived as intolerably loud or even painful. Despite the apparent link between pain and hyperacusis in humans, little research has been conducted directly comparing the presence of inflammation along the auditory pathway and the occurrence of hyperacusis. One of the major factors limiting this research has been the lack of a reliable animal behavioral model of hyperacusis. However, using reaction time measurements as a marker for loudness perception, I have successfully assessed rats for drug-induced hyperacusis and, more recently, noise-induced hyperacusis. Briefly, the animals will be trained to detect noise bursts of varying intensity. As in humans, the rats will respond faster with increasing sound intensity. Following drug administration or noise exposure, rats will be deemed to have hyperacusis if they have faster-than-normal reaction times to moderate and high-level sounds. Therefore, the goal of the proposed research is to correlate the presence of pain-related molecules along the auditory pathway with reliable behavioral measures of drug and noise-induced hyperacusis.

Mass Eye and Ear, Harvard Medical School
Homeostatic modifications in cortical GABA circuits enable states of hyperexcitability and reduced sound level tolerance after auditory nerve degeneration

Sensorineural hearing loss due to noise exposure, aging, ototoxic drugs, or certain diseases reduce the neural activity transmitted from the cochlea to the central auditory system. These types of hearing loss often give rise to hyperacusis, an auditory hypersensitivity disorder in which low- to moderate-intensity sounds are perceived as intolerably loud or even painful. Previously thought as originating in the damaged ear, hyperacusis is emerging as a complex disorder. While it can be triggered by a peripheral injury, it develops from a maladaptation of the central auditory system to the peripheral dysfunction. My research will test the hypothesis that the recovery of sound detection and speech comprehension, may cause an overcompensation that leads to an increase in sound sensitivity and reduced tolerance of moderately loud sounds.

This hypothesis will be tested using a combination of chronic single-unit recordings, operant behavioral methods and optogenetic interrogation of specific sub-classes of cortical interneurons. By understanding how brain plasticity is modulated, we will gain deeper insight into the neuronal mechanism underlying aberrant sound processing and its potential reversal.

Washington University in St. Louis

Preventing or mitigating hyperacusis with blockade of calcium-permeable AMPA receptors

Pain hyperacusis is an abnormal sound level tolerance associated with increased activity in the central auditory system. It can be caused by damage to the inner ear that is not detected on a typical hearing test. This type of damage is associated with permanent loss of cochlear nerve fibers. Paradoxically, in some patients this decrease in cochlear function leads to an increase in the brain’s sensititivity to sound. We have developed a therapy in mice to prevent loss of nerve fibers during noise trauma by inhibiting the synaptic communication between the cochlea and the auditory nerve. Importantly, animals can still hear during the protection because the communication is not blocked entirely. However, it is not known if preventing cochlear nerve loss would prevent the development of hyperacusis. We call our therapy “chemical earmuffs.”

The brain also has synapses that are inhibited by our chemical earmuffs. However, it is not known if inhibiting those could mitigate hyperacusis after it has emerged. If loss of input to the brain is responsible for the increase in activity in the central auditory system, then preventing this loss could prevent hyperacusis in the first place. If overactivity in the brain depends partly on activation of synapses inhibited by chemical earmuffs, then blocking them could mitigate active hyperacusis. Our small molecule therapy works when given systemically because it enters the inner ear and the brain from the blood. In this proposal, we hypothesize that (1) Preventing loss of cochlear nerve fibers will eliminate the development of hyperacusis, and (2) Giving our therapy to animals with hyperacusis will mitigate hyperacusis-associated phenotypes.

Johns Hopkins University School of Medicine
Type II auditory nerve fibers as instigators of the cochlear immune response after acoustic trauma

A subset of patients with hyperacusis experience pain in the presence of typically tolerated sound. Little is known about the origin of this pain. One hypothesis is that the type II auditory nerve fibers (type II neurons) of the inner ear may act as pain receptors after exposure to damaging levels of noise (acoustic damage). Our lab has shown that type II neurons share key characteristics with pain neurons: They respond to tissue damage; they are hyperactive after acoustic damage; and they express genes similar to pain neurons, such as the gene for CGRP-alpha. However, type II neurons are not the only cell types that respond to acoustic damage. The immune system responds quickly after damaging noise exposure. In other systems of the body such as the skin, CGRP-alpha can affect immune cell function. This project looks at the expression of CGRP-alpha in type II neurons after noise exposure. CGRP-alpha will be blocked during noise exposure to see if this affects the immune response to tissue damage.