HHF Emerging Research Grant Recipients Studying Tinnitus
Over the years, HHF has supported several research projects focused on tinnitus and noise-induced hearing loss. A sampling of funded projects of recent years includes:
Zhengquan Tang, Ph.D., 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.
Elizabeth A. Hurd, Ph.D., University of Michigan
Investigating the role of Chd7 during noise-induced hearing loss
Mice born with loss of Chd7, the gene mutated in human CHARGE syndrome, exhibit middle ear defects and resistance to acoustic trauma. Preliminary results show that deletion of Chd7 in adult mice (using tamoxifen inducible Cre line) also results in variable resistance to acoustic trauma, even in the absence of middle ear defects. This suggests important functions for Chd7 in regulating hair cells and neuronal integrity in adult cochlea. The objective of this research is to identify how loss of Chd7 influences susceptibility to acoustic trauma in the mature cochlea.
Debashree Mukherjea, Ph.D., Southern Illinois University School of Medicine
Targeting inflammation in prevention and treatment of noise-induced hearing loss (NIHL)
NIHL is a significant problem in the United States, affecting all age groups. Mukherjea’s research focuses on the inflammatory response of the cochlea due to noise trauma and will attempt to identify inflammatory targets involved in the development of NIHL, the inhibition of which (via localized or systemic treatment) will help ameliorate NIHL.
Adrian Rodriguez-Contreras, Ph.D., The City College of New York
Defining the role of olivo-cochlear feedback in the development of the auditory brainstem
During early brain development auditory neurons spontaneously generate highly patterned electrical activity in the absence of sound. In this project Rodriguez-Contreras will explore the role of cholinergic brainstem neurons in modulating the patterns of spontaneous activity. His work could provide clues to develop treatments that ameliorate hearing impairments such as tinnitus and deafness.
Sonja Pyott, Ph.D., University of North Carolina Wilmington
Enhancement of the Efferent-Hair Cell Synapse by Metabotropic Glutamate Receptors
This proposal aims to improve our understanding of the molecular mechanisms regulating synapses in the cochlea and will specifically characterize how a class of molecules, metabotropic glutamate receptors (mGluRs), regulates the efferent-hair cell synapses. Sensory hair cells of the cochlea communicate with the brain at specialized sites called synapses. Inner hair cells have numerous afferent synapses that relay information about sound from the hair cell to the brain. In contrast, outer hair cells are characterized by efferent synapses from the brain that regulate hair cell activity. Although these efferent and afferent synapses are normally considered to be independent from one another, experiments studying immature inner hair cells suggest that glutamate, the neurotransmitter required for transmission at the afferent synapse, may also modify the response of the efferent synapse. Efferent innervation of the cochlea is thought to protect against noise-induced hearing loss. Considering that noise-induced hearing loss accounts for one-third of all cases of deafness, understanding the mechanisms regulating efferent synapses is of special clinical relevance. This project will investigate this hypothesis and should uncover novel pharmaceutical targets to modulate the efferent synaptic response to either dampen hair cell activity and prevent noise-induced hearing or boost hair cell activity and combat deafness.
National Institute on Deafness and Other Communications Disorders (NIDCD)
In 2009, NIDCD funded its second-ever, phase III clinical trial award to support the Tinnitus Retraining Therapy Trial (TRTT). The TRTT is a multi-center, placebo-controlled, randomized trial to test efficacy of Tinnitus Retraining Therapy in people with primary, debilitating tinnitus.
TRT is a non-medical intervention that is implemented with directive, informational counseling and low-level sound therapy (usually achieved with sound generators worn on the ear). These components are combined in treatment protocol to habituate the patient’s associated negative emotional reactions (annoyance) to tinnitus, its perception (awareness) and ultimately its impact on the individual’s life. In other words, if the TRT-induced habituation process is successful, then at the end of treatment the patient will no longer be bothered or distressed by tinnitus. This is true even though the patient may still hear the sounds of tinnitus, but it is now a neutral signal the patient can ignore.
Currently recruiting participants, the tinnitus retraining therapy trial is a large scale, well-funded examination of potentially the most promising therapy for chronic tinnitus.
Other NIDCD research on tinnitus
Along the path a hearing signal travels to get from the inner ear to the brain, there are many places where things can go wrong to cause tinnitus. If scientists can understand what goes on in the brain to start tinnitus and cause it to persist, they can look for those places in the system where a therapeutic intervention could stop tinnitus in its tracks.
In 2009, the NIDCD sponsored a workshop that brought together tinnitus researchers to talk about the condition and develop fresh ideas for potential cures. During the course of the workshop, participants discussed a number of promising research directions, including:
Electrical or magnetic stimulation of brain areas involved in hearing. Implantable devices already exist to reduce the trembling of Parkinson’s disease and the anxieties of obsessive-compulsive disorder. Similar devices could be developed to normalize the neural circuits involved in tinnitus.
Repetitive transcranial magnetic stimulation (rTMS). This technique, which uses a small device placed on the scalp to generate short magnetic pulses, is already being used to normalize electrical activity in the brains of people with epilepsy. Preliminary trials of rTMS in humans, funded by the NIDCD, are helping researchers pinpoint the best places in the brain to stimulate in order to suppress tinnitus. Researchers are also looking for ways to identify which people are most likely to respond well to stimulation devices.
Hyperactivity and deep brain stimulation. Researchers have observed hyperactivity in neural networks after exposing the ear to intense noise. Understanding specifically where in the brain this hyperactivity begins and how it spreads to other areas could lead to treatments that use deep brain stimulation to calm the neural networks and reduce tinnitus.
Resetting the tonotopic map. Researchers are exploring how to take advantage of the tonotopic map, which organizes neurons in the auditory cortex according to the frequency of the sound to which they respond. Previous research has shown a change in the organization of the tonotopic map after exposing the ear to intense noise. By understanding how these changes happen, researchers could develop techniques to bring the map back to normal and relieve tinnitus.
American Tinnitus Association (ATA)
Since the 1980’s, the ATA has funded over 100 tinnitus research projects. ATA is currently funding six research projects
which focus on testing different treatment options and identifying root causes of tinnitus.
Research on Tinnitus Treatments
Sound therapy: Various types of sounds have been used in managing tinnitus, ranging from white noise to one’s favorite music. Sounds can be delivered using different devices to suit different environments. Amplified neutral sounds through hearing aids are also shown to be effective in reducing tinnitus in patients that have hearing loss and tinnitus. Researchers have recently studied effects of sounds of particular patterns (including SoundCure and Acoustic CR Neuromodulation) that are designed to counteract the very brain activities that generate tinnitus perception and to eliminate tinnitus, rather than “masking” it. Preliminary results are encouraging and ongoing trials are under way. Yet, while sound therapy has been explored in many studies, only a few of these studies are well controlled. Some reviews conclude that, although safe, the value of sound therapy itself remains to be confirmed due to its often combined use with other treatments.
Drug therapy: Medications including sedatives, anti-seizure agents, antidepressants, hypnotics, anesthetics, steroids, vasodilators (which open up blood vessels), nutritional supplements, and homeopathic agents have all been explored for their potential benefits in treating tinnitus, with minimal to moderate, variable, and often controversial results. In general, medications for tinnitus are usually used to address accompanying problems – such as irritability, sleep difficulties, and depression – instead of the tinnitus itself. Well-controlled drug trials for tinnitus are limited. Although nortriptyline (Pamelor) has been suggested to be beneficial in patients with tinnitus and depression, there is insufficient study evidence to say that antidepressant therapy in general improves tinnitus. Alprazolam (Xanax) has been shown to reduce tinnitus loudness in nearly 80 percent of study subjects in two small studies (fewer than 50 subjects each). Studies on intratympanic injection of steroids (steroids injected into the middle ear) have shown inconclusive or conflicting results in tinnitus patients. Recent trials of anti-seizure medications including gabapentin (Neurontin) have either failed to provide sufficient evidence to prove its superiority over the placebo or shown small effects that may not be clinically significant. There is no reliable research evidence to support food supplements or homeopathic agents in treating tinnitus. The herbal supplement ginkgo biloba is repeatedly who to be no better than a placebo in large-scale clinical trials.
Psychological interventions: As the role of psychological dysfunction in chronic tinnitus is increasingly recognized, psychological interventions, in addition to routine patient education and counseling, have been regarded as an important part of tinnitus management. Specific attention has been focused on cognitive-behavioral therapy (CBT) in recent years. Several studies have suggested that CBT improves tinnitus, although there is also research that shows it has no effect on tinnitus loudness. Most studies agree that CBT improves the patient’s general well-being and quality of life, and that the effects can be maintained over time. More trials are currently under way to establish its efficacy as a valid tinnitus treatment. Additionally, the patient education and counseling components in TRT (see above) and other habituation therapies may very well play a role in psychological intervention. Studies seem to indicate that TRT is superior over simple masking which may be attributed to the additional psychological benefits from patient education and counseling.
Brain stimulation: It has been theorized that manipulation of activities in relevant areas of the brain may affect tinnitus. Deep brain stimulation, transcranial magnetic stimulation, and direct brain stimulation have been studied for their effects on tinnitus. Transcranial magnetic stimulation is a noninvasive procedure that changes neural activity in brain tissue within the magnetic fields generated by coils placed outside the skull. On the other hand, deep brain stimulation and direct brain stimulation require direct access to the stimulation target in the brain and are therefore associated with risks and complications normally seen in brain surgeries. Functional brain imaging has been reported in some studies to facilitate locating the stimulation target. Pilot studies have indicated benefits from transcranial, deep brain, and direct brain stimulation in some patients. But the limited number of studies and cases reported, as well as the invasive nature of some of these procedures, means there is very limited support for their routine use in patients with tinnitus. Some studies also suggest that electric stimulation via cochlear implantation can reduce tinnitus in patients with profound hearing loss. Electrical nerve stimulation is shown to have limited effects on tinnitus, but seems to improve quality of life. Nontraditional interventions including acupuncture, hyperbaric oxygen therapy (inhaling concentrated oxygen in a pressurized chamber), and low-level laser irradiation treatment through the ear canal have been tested for their potential benefits in the treatment of tinnitus. Yet, there is insufficient study evidence to support their respective efficacies.