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.

University at Buffalo, the State University of New York
Targeting microglial activation in hyperacusis

Hyperacusis is a hearing condition in which moderate-level noise becomes intolerable. The Centers for Disease Control estimates that nearly 6 percent of the U.S. population experiences some form of hyperacusis, ranging from mild discomfort to severe medical disability, with a diminished quality of life. There is currently no cure for hyperacusis. Therefore, there is a pressing medical need for targeted treatment approaches for the permanent relief of hyperacusis. This study will focus on the involvement of inflammation in the sound processing centers of the brain following noise exposure by using anti-inflammatory drugs to attempt to reduce inflammation and prevent hyperacusis after noise exposure. Results from this study will test the feasibility of anti-inflammatory drugs as a potential therapy for hyperacusis and hearing loss caused by excessive noise exposure.

University at Buffalo

FOXG1 gene mutation-caused hyperacusis—a novel model to study hyperacusis

Hyperacusis is a common symptom in children with neurological disorders such as autism spectrum disorder, Williams syndrome, Rett syndrome, and FOXG1 syndrome (FS). The cause of hyperacusis in these neurological disorders has not been fully discovered. FOXG1 mutation is a recently defined, rare and devastating neurodevelopmental disorder. MRI studies show a spectrum of structural brain anomalies, including cortical atrophy, hypogenesis of the corpus callosum, and delayed myelination in children with FS. However, the impact of the FOXG1 mutation on the central auditory system and hyperacusis is largely unknown. Children with FS show signs of hyperacusis, including becoming startled, upset, and even experiencing seizures from loud sounds. The mouse model of FOXG1 mutation provides a novel model to study neurological dysfunction in the central auditory system resulting in hyperacusis. In this project, we will use a mouse model developed by colleagues at University at Buffalo that replicates gene mutations in FS children to study hyperacusis. In our preliminary studies, we found that the mutant mice showed a lack of habituation in the startle tests and an aversive reaction to loud sounds in the open field test. We also found that the cortical neurons showed reduced neural activities and prolonged responses to sound stimuli, suggesting hypoexcitability and a lack of adaptation to sound stimuli. The results point toward a novel neurological model of hyperacusis compared with the current “central gain” theory. Our findings will provide mechanistic insights into the role of the FOXG1 gene on hyperacusis and shed light on detecting potential therapeutic targets to alleviate hyperacusis caused by FS and other neurological disorders.

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.