Oregon Health & Science University
Chronic transmitter exposure in excitatory neurons of the cochlear nucleus generates persistent excitation and could underlie tinnitus

The dorsal cochlear nucleus in the brainstem receives not only auditory signals directly from the ear but also multisensory input from other areas of the brain. However, the sources of these inputs are unclear. We do know the inputs are processed through unipolar brush cells (UBC), a type of nerve cell in the cochlear nucleus that amplifies signals. This cell derives its name from its single paintbrush-like dendrite, which shows persistent excitation due to chronic neurotransmitter exposure. My project is to investigate whether problems with the multisensory inputs or with the chronic neurotransmitter at the UBC synapse lead to hyperactivity of the cochlear nucleus, which is associated with tinnitus.

University of Texas at Austin
Auditory gating in tinnitus

Tinnitus is the perception of sound, such as ringing or buzzing, without an external source. Though tinnitus likely arises, in part, from hearing loss in the inner ear, research has determined that the ongoing perception of tinnitus occurs in the brain. It has been suggested that auditory gating, a function carried out by the brain in filtering out unimportant auditory information, may be abnormal in individuals with tinnitus and contribute to the conscious perception of the phantom sound.

Auditory gating can be measured noninvasively through the brain’s cortical response to sound during recording of brainwave activity, known as EEG (electroencephalography). In typical auditory gating function, cortical auditory evoked potentials (CAEPs) recorded during EEG show a decrease in amplitude when sounds (e.g., tone pairs) are presented close together in time. This decrease in amplitude reflects the brain’s ability to filter out repetitive auditory input. In atypical gating function, CAEP amplitude remains the same across sound presentation or shows little change, again suggestive of the brain’s inability to filter out irrelevant input.

This study aims to evaluate auditory gating processes in tinnitus, including cortical sources of active gating networks as observed through source localization analyses. These results will be correlated with subject reports of tinnitus severity.

University at Buffalo, the State University of New York
Noise-induced tinnitus in mice

Animal models of tinnitus have employed many different behavioral techniques, only one of which is not subject to motivational issues and changes in auditory acuity. Tinnitus has previously been induced in rats following a sodium salicylate injection. In the present proposal, this paradigm will be modified to investigate tinnitus in mice. These experiments as a whole aim to determine the time course of tinnitus and its recovery following nontraumatic noise exposures in mice. Until there is an objective measure that separates hearing loss from tinnitus, it is difficult to use mice to study tinnitus. This project seeks to define a way to measure and characterize tinnitus in the awake and behaving mouse model in order to compare this to humans with tinnitus.

Massachusetts Eye and Ear, Harvard Medical School
Mechanisms and development of novel small molecule treatments for cochlear synaptopathy

Inner ear sensory hair cells detect sound vibrations in the inner ear and pass these signals to inner ear neurons, which ultimately send the signals to the brain. The synaptic connections between inner hair cells and neurons (nerve cells) can be lost from noise exposure, aging, or both. The loss of these connections results in what has been termed “hidden” hearing loss because it may be undetected via traditional auditory measures, and it may also be associated with other hearing disorders such as tinnitus and hyperacusis. To reestablish synaptic connections, we have developed a novel way to anchor special molecules that promote synaptic regeneration into the bone of the inner ear, to maximize the stimulation of inner ear neurons.

University of California, Irvine
Objective and subjective suprathreshold measures of auditory neurodegeneration

Recent research on animals convincingly demonstrates that degeneration of the auditory nerve, called auditory neurodegeneration, will result from a brief, moderate noise exposure. These animals suffered from severe, permanent deterioration of the function and microscopic appearance of the auditory nerve from a seemingly short, innocuous noise exposure. Interestingly, the animal’s ability to recognize the presence of sound fully recovered to normal threshold levels following the trauma.

However, when presented with sound levels above their ability to hear (“suprathreshold” levels), the strength of the electric signals from the auditory nerve was reduced by as much as 50 percent in some frequencies. Because standard hearing tests (audiograms) of these noise-exposed animals were indistinguishable from unexposed animals, the phenomenon of auditory neurodegeneration may result in a “hidden hearing loss,” and moreover, play a key role in the development of tinnitus, hyperacusis, and other auditory processing abnormalities.

Many military personnel who are subject to severe noise trauma and blast injuries subsequently develop chronic, oftentimes debilitating, tinnitus, and it is thought that this auditory neurodegeneration phenomenon is at least partially responsible for these symptoms. But auditory neurodegeneration in humans has not been established, and its perceptual consequences, including tinnitus, remain unknown. This project aims to establish the missing link between animal and human studies on auditory neurodegeneration and to provide quantitative and qualitative assessment of perceptual consequences of neurodegeneration.

Oregon Health & Science University
Discovery of novel inhibitory cell types in the cochlear nucleus

Excessive neuronal electrical activity, or hyperactivity, is believed to underlie tinnitus. While many studies on hyperactivity have focused on a region called the dorsal cochlear nucleus, an auditory processing region in the brainstem, very little attention has been given to the ventral cochlear nucleus (VCN). This is surprising since the VCN is likely required for the activation of higher auditory centers in the brain. One likely cause of hyperexcitability is an imbalance between excitatory and inhibitory neuronal connections, or synapses. With the use of genetically modified mouse lines, we are able to reveal that the diversity of inhibitory cell types and circuitry within the VCN is far richer than previously described. Our primary goal is to discover and study the functional significance of these novel inhibitory neurons in the VCN whose inhibitory action, if compromised, could lead to hyperactivity and auditory dysfunction.

Oregon Health & Science University
Hyperexcitability dependent on Neuromodulatory state in the cochlear nucleus

Tinnitus affects approximately 50 million people in the USA, and millions more worldwide. However, the mechanisms underlying tinnitus are poorly understood. The dorsal cochlear nucleus (DCN), one of the first stations of the ascending auditory pathway, receives dense serotonergic input. Recent evidence indicates that the DCN may be a site of central tinnitus, and it is possible that serotonin might play a role in the generation or modulation of central tinnitus. Moreover, serotonin reuptake inhibitors (SSRIs) typically used as antidepressants in the treatment of depression and anxiety disorders, have been explored as a treatment for tinnitus. The goal of this research is to identify the cellular targets of serotonin and SSRIs in the DCN and understand their functional roles. The ultimate goals of this research are to understand how serotonin influences the output of the DCN, and whether serotonin may have a role in tinnitus.

Research area: Tinnitus

Long-term goal of research: To understand how different neuromodulators control the neural activity in the central auditory system and their role in pathological auditory processing.

University of Iowa
Literature review on hyperacusis, recruitment, misophonia, phonophobia, and mechanisms

The funded research will result in a thorough review of the literature, documenting causes, mechanisms, measurement and treatment. It is the intent that the review will provide a comprehensive document that clinicians and researchers will be able to use to understand hyperacusis and to improve current treatment approaches, and to suggest future treatment directions.

Research areas: cochlear implants, tinnitus

Long-term goal of research: The long-term goal is to provide a systematic, comprehensive review of the entire field of hyperacusis. By providing such a widespread and comprehensive review of hyperacusis, we should be able to provide the background necessary to direct research to find cures.

University of Michigan
Development and transmission of the tinnitus neural code

Noise overexposure is a common risk factor of tinnitus, and is thus used as a common tinnitus inducer in animal research. However, noise exposure does not always cause tinnitus, and researchers would rely on behavioral testing to infer an animal’s subjective pathology. However, behavioral tests only work under the assumption that tinnitus is unchanging during the long testing period, which does not reflect the dynamic nature of tinnitus as well as ignoring variability. This inability to measure tinnitus within a short time window impedes our understanding of its emergence and progression. The project addresses these limitations through bypassing behavioral testing and directly identifying and locating an objective code for tinnitus in real-time spiking neurons. Using a novel data-driven approach, we can pinpoint exactly when/where tinnitus emerges and examine how noise trauma triggers and transmits the tinnitus signal throughout the auditory pathway.

Howard University
Dopaminergic activity in modulation of noise-induced tinnitus

Tinnitus is a major challenge for public health because it is a condition that is associated with hearing loss and can contribute to debilitating emotional stress, anxiety, and mental fatigue. Dr. Zhan’s interest is focused on the mechanisms that generate tinnitus and modulate tinnitus associated anxiety and depression using an animal model. His studies focus on dopaminergic activity in the limbic midbrain. Dopamine and its receptors play an important role in human mood behavior. Recently, dopamine has been suggested to be involved in tinnitus. Dr. Zhan’s research is designed to find out how dopamine neurons are communicating with other neurons to contribute to tinnitus generation. In addition, he also investigates how the functions of dopamine cells are modified during the development of tinnitus following noise exposures. These studies will shed light on the cellular mechanisms of tinnitus and offer a novel avenue for drug therapy.