Mass Eye and Ear

Auditory-limbic circuit dynamics as therapeutic targets in hyperacusis

Our research addresses a critical gap in understanding the neural basis of hyperacusis by focusing on the emotional dimensions of sound hypersensitivity. Previous work has established that cochlear damage leads to hyperexcitability throughout the central auditory pathway, but our approach uniquely focuses on the circuit-specific mechanisms that link auditory processing to emotional responses.

Specifically, we investigate how noise-induced hearing loss affects two parallel pathways to the lateral amygdala: the cortico-amygdalar (CAmy) and thalamo-amygdalar (TAmy) projections. This pathway- specific investigation represents a novel approach to understanding hyperacusis, as it targets the precise neural circuits that may mediate both the perceptual and emotional components of this disorder.

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.

University of Pittsburgh

KCNQ2/3 potassium channel activator mitigates noise-trauma–induced hypersensitivity to sounds
in mice

Noise-induced hearing loss (NIHL) is one of the most common causes of hearing disorders. NIHL reduces the auditory sensory information relayed from the cochlea to the brain, including the primary auditory cortex (A1). To compensate for reduced peripheral sensory input, A1 undergoes homeostatic plasticity. Namely, the sound-evoked activity of A1 excitatory principal neurons (PNs) recovers or even surpasses pre-noise trauma levels and exhibits increased response gain (the slope of neuronal responses against sound levels). This increased gain of A1 PNs after NIHL is associated with highly debilitating hearing disorders, such as tinnitus (perception of phantom sounds), hyperacusis (painful perception of sounds), and hypersensitivity to sounds (increased sensitivity to everyday sounds). Despite the high prevalence of these hearing disorders, treatment options are limited to cognitive behavioral therapy and hearing prosthetics with no FDA-approved pharmacotherapeutic options available. Therefore, to aid in the development of pharmacotherapeutic options, it is imperative to 1) develop animal models of these hearing disorders, 2) identify the brain plasticity underlying these hearing disorders, and 3) test potential pharmacotherapy to rehabilitate hearing and brain plasticity after NIHL. Here, we aim to develop a novel mouse model of hypersensitivity to sounds, identify its underlying A1 plasticity, and test pharmacotherapy to mitigate it after NIHL.

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.

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.