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A Cure for Tinnitus
 
Tinnitus is associated with hearing loss that itself results from damage to the cochlea, and more specifically to the organ of Corti.
 
This organ is an epithelium that contains the sensory hair cells required for hearing, and the loss of hair cells leads to a reduction in hearing. Missing hair cells are also thought to set up a persistent imbalance in the cochlea that can be interpreted by the brain as sound even when no auditory signal is present in the environment. This, in fact, is the definition of tinnitus: hearing a sound that has no external auditory source.
 
Of course, it is not as simple as that. Not everyone with hearing loss has tinnitus, for reasons that are unclear.
 
In addition, not everyone with tinnitus has an abnormal audiogram. In these cases, it is thought that individuals who have audiologically normal hearing but who suffer from tinnitus have more subtle damage to one or more restricted regions of the cochlea that are not tested by a standard audiogram. In such cases, tinnitus could be due to damage to frequencies above 8,000 Hz, which are not routinely tested, or “microlesions” in small areas of the sensory epithelium, in between those that encode standard audiometric frequencies.
 
If damage to the hair cells in the organ of Corti is associated with tinnitus, this naturally leads to the question: If the organ were repaired, would the associated tinnitus be cured or improved? The answer to this is of course unknown. Animal studies are difficult as it is hard to know for sure whether an animal has tinnitus (see “The Importance of Animal Models”). And at present we cannot repair damage to hair cells in humans and so cannot currently conduct clinical trials in humans with tinnitus.
 
The Hearing Restoration Project (HRP) may have a solution. It is developing procedures for the repair of the sensory epithelium of the cochlea by replacing hair cells that have been lost in the organ of Corti. This groundbreaking project brings together scientists around the world (the U.S., Canada, and the U.K.), researchers who are pooling their expertise and knowledge to solve the problem of hair cell regeneration.
 
While it is known that birds and fish can spontaneously replace lost or damaged hair cells, this does not happen in mammals, including humans. The HRP consortium is working to discover the conditions and factors that would allow human hair cells to be restored, either by the generation of new cells in the organ of Corti, or by the conversion of nonsensory cells into hair cells.
 
HRP scientists are also exploring the potential of stem cells, those renewable and flexible cells that can adopt many different cellular characteristics, to become hair cells and be transplanted into the inner ear.
 
This research could lead, for the first time, to a biologic cure for hearing loss. Although there is much additional work to be done before hearing can be restored to patients with hearing loss, we are seeing promising results (see “A New Treatment Restores Hearing in Mice,” in the Spring 2013 issue).
 
Let’s assume (as we certainly do!) that the HRP will lead to a successful method for hair cell regeneration and the recovery of hearing in humans. Can this also cure tinnitus?
 
There is certainly evidence that the restoration of hearing can alleviate tinnitus. For example, tinnitus can be induced by exposure to loud sounds that result in the temporary loss of hearing, which is experienced by many after attending a loud event like a rock concert. In most such cases, the tinnitus disappears as the hearing recovers.
 
Another example is the response of patients for whom otosclerosis (an abnormal bone growth in the middle ear) has induced a conductive hearing loss. Many such patients with this hereditary condition experience tinnitus. However, when their hearing is restored through a stapedectomy, a surgical procedure, many report an improvement in tinnitus (see “About Otosclerosis”).
 
Finally, there have been several reports that patients, after receiving a cochlear implant, experience a significant reduction in their tinnitus. Interestingly, in some cases this tinnitus suppression continues for several hours after the implant is turned off. Though the mechanism by which cochlear implants may suppress tinnitus is not clear, these observations all suggest that restoring function to the auditory system may be very helpful for tinnitus in a variety of ways.
 
Hearing restoration may be especially helpful for tinnitus of recent origin. It has been suggested that while tinnitus begins in the cochlea due to hair cell damage, over time it appears to set up circuits in the brain which can be independent of the inner ear. Such long-term tinnitus may not be reduced in apparent intensity by repair of the organ of Corti.
 
That said, we cannot conclusively know the effects of repairing the hair cells in the organ of Corti that restore hearing until mammalian restoration of inner ear hair cells is achieved. It is even possible that the central auditory system can be retrained over time, leading to a reduction in long-standing tinnitus. The potential for masking long-term tinnitus or reducing its annoyance factor will still be a positive benefit from hearing restoration.
 
The HRP has the potential to not only ameliorate hearing loss but also to potentially cure many types of tinnitus.
 
Allen F. Ryan, Ph.D., is a professor and the director of Research in the Division of Otolaryngology in the University of California, San Diego, School of Medicine in La Jolla. His laboratory studies mechanisms of cochlear damage as well as new therapies for hearing loss, and he has served for many years on the advisory board of  the Tinnitus Research Consortium, that supported research on tinnitus.
 
About Otosclerosis
Otosclerosis is a hereditary disease that leads to an overgrowth of bone in the ear. When it occurs in the middle ear, it can block sound from entering the inner ear, resulting in hearing loss. Many patients with otosclerosis also suffer from tinnitus.
 
However, unlike many forms of hearing loss, the majority of the loss in otosclerosis can be corrected by a surgical procedure that replaces the damaged bones of the middle ear with a prosthetic device. When the hearing of otosclerosis patients is surgically restored, the majority report that their tinnitus has either disappeared or greatly improved. This finding suggests that restoration of hearing by hair cell regeneration, the goal of the HRP, may well lead to reduction in or elimination of tinnitus. —A.F.R.
 
Read more on Otosclerosis.
 
The Importance of Animal Models
Scientists studying the mechanisms of tinnitus in order to devise therapeutic treatments require animal models that not only experience tinnitus but also have reactions to tinnitus similar to those of humans.
 
While the buzzing or ringing of tinnitus is the primary manifestation, suffering from tinnitus is thought to be related principally to the emotional or autonomic reactions to tinnitus. Emotional reactions to tinnitus are manifested as stress, anxiety, depression, and insomnia. Autonomic reactions, which can thought to be physical reactions, may in animals include increased heart rate, high blood pressure, irregular heart rate, tremors, or spasms in the respiratory or digestive systems.
 
The behavioral animal models developed over the past 25 years are based on the assumption that animals trained to respond in a particular way during silent intervals will respond differently when they perceive a sound. These have been refined to elicit responses showing avoidance of unpleasant experiences, identification of the direction of the perceived tinnitus source, and poorer detection of silent gaps in noise similar to their tinnitus.
 
The current need is for an animal model that can display an emotional reaction or physical response to tinnitus. For example, fear conditioning to tinnitus could be used to demonstrate anxiety or another emotional or physical response. Measuring these reactions will permit the testing of drugs and other interventions to modify or extinguish them, even if the perception of tinnitus cannot be eliminated.
 
The first attempt to develop such an animal model is being carried out at Johns Hopkins University Medical Institutions supported by a contract from the Tinnitus Research Consortium. Bradford J. May, Ph.D., a preeminent behavioral psychologist, is leading this effort. The accomplishment of this objective by May and his team is likely to initiate the development and validation of additional similar models for the specific research needs of other investigators engaged in leading-edge tinnitus research.
 
James B. Snow, Jr., M.D., editor of “Tinnitus: Theory and Management,” the inspiration for this special issue of Hearing Health magazine.
 
 
 
 
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