Center for Hearing and Deafness: Overview

Twenty-eight million Americans, nearly 10 percent of the U.S. population, have lost the ability to hear clearly. As the baby-boom bulge passes into seniorhood and the current elderly population lives longer, that percentage is destined to increase significantly.

This public health problem doesn't come cheap. A policy analysis prepared by Project Hope estimates the societal cost of serving the hearing impaired at $297,000 per person (in 1998 dollars) over a lifetime, based on costs of evaluation and treatment and lost earnings. These figures do not include the costs of social isolation and psychological stress, a particular problem for the elderly, who represent 40 percent of new cases.

Some of the newest research into how we hear and what happens when we don't is being conducted at The Center for Hearing and Deafness at the University at Buffalo. The center was established in 1995 by Richard Salvi and Donald Henderson, accomplished hearing researchers who came to UB in late 1987 from the University of Texas at Dallas.

In this multidisciplinary laboratory specialists in anatomy, audiology, biophysics, engineering, otolaryngology, pediatrics, neurology, physiology, pharmacology and psychology are conducting studies in hair cell regeneration, drug therapy and ototoxic drugs, noise-induced hearing loss, middle ear disease, infant hearing loss, central auditory system plasticity, mechanical transduction (the fundamental process of transferring sound energy to electrical energy), age-related hearing loss, hormonal influence on hearing loss, and central auditory processing in the brain.

Center scientists have generated more than $12 million in research funding, including a highly-competitive $5.7 million multidisciplinary program project grant from the National Institutes of Health awarded in 1999, which focuses specifically on the mechanisms underlying acquired hearing loss.

Why is a large segment of the population becoming "hard of hearing"?

About 10 million can attribute their loss of hearing to noise exposure. Listening to music through stereo headphones at top volume, for example, is as damaging to the auditory system as the thunder of a diesel locomotive. Thirty million people in the U.S. are exposed to similarly dangerous noise levels each day.

Infections and some cancer chemotherapy drugs also can cause deafness, but the major culprit is Father Time. The National Institute on Deafness and Other Communicative Disorders estimates that 30-to-35 percent of people between the ages of 65 and 75 have a hearing loss. The percentage climbs to nearly 50 percent among those over 75.

For much of the 20th century, technology to improve hearing had advanced little beyond the ear trumpet, a large cone-shaped megaphone-in-reverse that was intended to amplify sound to the ear. That was state-of-the-art for our hard-of-hearing great-grandparents.

Richard Salvi, Ph.D., professor of communicative disorders and sciences, neurology and otolaryngology and director of the center, says that until the last five -to-eight years, people looked at hearing loss from a descriptive point of view. "They measured loss; how poor people were at detecting speech and other sounds, and how well they could hear in a background of noise," he says. "That's been the situation for basically the past 100 years."

Only within the past two decades have hearing researchers begun to understand that hearing depends primarily on the ability of tiny cilia on hair cells of the inner ear to transform sound-wave energy into electrical energy, and on how accurately the brain receives and translates the resulting nerve impulses.

"The big change came with advances in biology and our ability to study how inner ear hair cells develop, live and die," Salvi says. "A huge amount of work is now being done in that area and our lab was one of the first to get involved. Hearing research has moved from the cellular to the molecular level to the genetic level."

Center scientists are responsible for several major advances in the field:

* Discovered several classes of compounds that may protect against noise-induced hearing loss

* Found a site in the brain associated with the ringing in the ears that affects up to 50 million people in the U.S alone.

* Discovered the existence of the so-called "line busy" signal in the inner ear, a phenomenon that leads to significant hearing loss in a manner unrelated to that caused by damage to the ear's sensory cells.

* Identified a protective function of the efferent system within the auditory system that affects the development of noise-induced hearing loss

* Completed ground-breaking studies in brain plasticity and antioxidant enzyme research

* Made major advances in understanding how inner ear hair cells can regenerate in certain birds, raising the possibility that hearing eventually can be restored in humans

* Is one of the first laboratories to conduct gene expression studies to determine the cell signaling pathways involved in noise-induced hearing loss.

* Discovered that toxic free radicals may be a common cause of hearing loss from aging, ototoxic drugs and noise exposure.

The center supports eight full-time researchers, approximately 10 doctoral students, six-to-eight post-doctoral fellows and several visiting scientists, and collaborates with investigators at research centers in England, France, Germany, Italy, and China; several universities in the U.S. and the National Institutes of Health.

Tracing the path of cell death

Most cases of hearing loss occur when inner ear hair cells in the cochlea are damaged or killed. Hair cells transfer their neural activity to the auditory nerve, which carries the nerve impulses to the brain's central auditory system. Considerable research in recent years has been devoted to finding compounds that might protect against hearing loss by preventing hair cell death or by rescuing and repairing damaged cells.

Center researchers, collaborating with colleagues at Roswell Park Cancer Institute, were among the first to study the process of hair cell death -- specifically programmed cell death called apoptosis - in inner ear hair cells. Salvi and fellow center scientists1 are attempting to determine what triggers the cell-death switch of apoptosis by subjecting cultured inner ear sensory cells and sensory neurons to known ototoxic drugs - the antibiotic gentamicin and cancer therapy drugs cisplatin or carboplatin - and tracking the biochemical pathways involved in cell death.

Armed with these findings, the researchers now are using certain drugs to try to block these pathways. The primary candidates are a protease inhibitor called leupeptin and an inhibitor of the tumor suppressor gene P53, which acts as a cell executioner, of sorts.

"Gentamicin is used in the U.S. to treat infections that arise in persons with muscular dystrophy and cystic fibrosis and is used extensively in other parts of the world to treat a wide range of bacterial infections, Salvi says. "Unfortunately, gentamicin causes severe deafness, so there is tremendous interest in finding drugs that block hair cell death.

"We have found that leupeptin does a tremendous job of rescuing cells exposed to gentamicin. In inner-ear cultures, we see 70 percent loss of hair cells without it, but with it we can rescue most of those cells. We've also shown that using a P53 inhibitor, we can block cisplatin toxicity in the inner ear."

Eri Hashino, Ph.D., a center research assistant professor and specialist in neuroscience, is studying the cellular mechanism thought to be responsible for the uptake of gentamicin into the hair cells. Her studies suggest that gentamicin is captured and sequestered in lysosomes, hair cell "garbage cans," for a period of time before it kills the hair cells. This finding sugegsts that lysosomes may be an important element in the cell death process and could be targeted for intervention.

Hair-cell death due to noise exposure is the primary focus of the work of Donald Henderson, professor of communicative disorders and sciences and otolaryngology. He and colleagues are conducting front-line investigations into compounds that may protect the auditory system from too much noise.

They have identified and are concentrating on a family of enzymes, some of which trigger the death process and some which execute it. "Now we are trying to trace the pathway of these enzymes to their starting point," says Henderson. "If we can do this, we can rescue, and perhaps prevent, hearing loss due to noise damage."

One enzyme being studied as a possible protectant is gluthathione peroxidase, a compound important for maintaining antioxidant activity, which in turn is essential for combating cell damage from free radicals. "We know noise can increase formation of free radicals in the cochlea," Henderson says. "We are investigating how this enzyme would work as a treatment in humans, and how and when to give the drug."

The role of genes and genetic variation

Center researchers led by Tom Taggart, Ph.D., associate professor of communicative disorders and sciences, are taking center stage in a new avenue of auditory research: the genetics of hearing loss. The center is one of the first to conduct gene expression studies identifying genes within the inner ear that are up regulated in response to intense sound stimulation. So far they have found about 100 genes that increase their expression substantially following three- to-six hours of moderate level noise exposure.

Initial studies indicate that even moderate noise exposure stimulates the repair and replacement of proteins in the inner ear, suggesting that if this repair process can be started early enough, it may be possible to condition the ear against hearing loss.

Taggart also is investigating the potential of inherited variation in DNA sequences of the inner ear to influence an individual's susceptibility to noise-induced hearing loss. These studies involve US Navy personnel who work in high-noise jobs. The studies are assessing the possible role of genetic variation within the specific inner ear proteins that maintain cellular homeostasis of the inner ear during and after noise exposure.

Taggart is targeting a group of functionally related proteins called connexins, which maintain normal functioning within the inner ear and are thought to be linked to noise induced hearing loss.

Hearing loss due to aging, responsible for the largest cohort of the hearing impaired, also may have a genetic component, an avenue Robert Burkard, Ph.D., professor of communicative disorders and sciences and otolaryngology is pursuing.

"Many hearing losses are genetically programmed to show up later in life,"says Burkard. "There is quite a bit of evidence to indicate that age-related hearing loss may be a result of a genetic inability to clean up free radicals. If we know that the gene turns on at, say, 60, we can be poised to do something about it. Once we have ideas concerning the causes, we are in a better position to approach a treatment or cure."

Pinpointing tinnitus

UB researchers have done ground-breaking research into tinnitus, the debilitating phantom sounds known as "ringing in the ears," which plague millions of persons, some to the point of disability. Alan Lockwood, Ph.D., professor of neurology, a member of the center faculty and director of UB's PET imaging center, which is operated jointly with Buffalo Veterans Affairs Medical Center, was the first to identify certain sites in the brain where tinnitus originates.

Lockwood, Salvi and Burkard now are studying volunteers who can change their tinnitus with certain eye or jaw movements to define further the brain regions that are involved. They also are investigating the effects of the painkiller lidocaine on tinnitus, says to reduce the symptoms by up to 30 percent in some sufferers.

"We are trying to determine what is causing tinnitus from the brain's perspective," says Burkard. "Why is the sound being modified? Do different parts of the brain light up? We're looking for areas less and more active that could be helping turn off tinnitus." Burkard, Salvi and Lockwood also are working with an experimental device that can interrupt or mask tinnitus in some subjects through the use of ultrasonic bone conduction.

In a related project, center researchers are capitalizing on PET's ability to track brain responses to stimuli to determine if different brain regions are activated during noise and quiet.

The pliable brain, the mysterious efferent system, and

a potential new role for estrogen

The research of several center researchers in the field of brain plasticity has more immediate clinical applications. It is known that the neuronal network responsible for hearing reorganizes itself after damage to inner hair cells; changes the channel to get better reception, in a sense.

Burkard says one explanation for this phenomenon may be that somewhere in the brain, the inhibition mechanism that protects the central auditory system from too much stimulus develops a lower threshold when less sound reaches the system. The brain's penchant for reorganizing itself may then explain why people who get hearing aids or implants often have trouble adjusting to the devices.

"When people first try a hearing aid, they frequently don't like it," Burkard says. "We think this is because the brain has already compensated for less stimulus, and when the signal is turned up with a hearing aid, it's bothersome; it helps to explain people's distress. This is why it is really important for people to stay with their devices until the brain once again adjusts to the new stimuli."

Sandra McFadden, Ph.D, research assistant professor at the center, and Henderson have found that a poorly understood segment of the auditory organs called the efferent system may play a role in permanent hearing loss.

"The efferent system is the appendix of the auditory system," McFadden says. "We don't really know what it does."

Anatomically, the efferent system is a large bundle of fibers running from the brain to the cochlea that functions as a feedback mechanism. "We're one of the first laboratories to show that if you cut the efferent fibers in one ear, those ears show more damage from noise," McFadden says. "It appears the efferent system may be important for hearing during noisy situations."

McFadden also is investigating the potential role of estrogen as a protectant against hearing loss. Hers is the first study to look at the hormone in this context. Working with chinchillas, she found that noise exposure caused less damage in animals receiving estrogen than in those that didn't. These results suggest that estrogen, like gluthathione peroxidase, may act as an antioxidant.

"Men get more noise-induced hearing loss than women, and they experience age-induced hearing loss earlier and more severely than women," McFadden says. "In part, this may be because men are exposed to more noise throughout life. But we are seeing some very similar sex differences in chinchillas."

In experiments conducted before and after administering estrogen, she found that the females were less susceptible to noise damage at baseline, and that animals receiving estrogen were less likely to develop hearing loss due to noise. She is now measuring natural estrogen levels in her animals and testing their susceptibility to noise.

Defining time and intensity patterns of sound

Most hearing research and treatment to date has concentrated on the "sending" end: transmitting auditory signals to the brain. However, it is possible for people to have trouble hearing even when the sending mechanism is in fine shape. One new and promising field of hearing research centers on how and where the brain receives and deciphers certain signals from the auditory nerve.

David Eddins, Ph.D. and Ann Clock Eddins, Ph.D., both associate professors in communicative Disorders and Sciences and also husband and wife, are conducting front-line research in this area. They work in the field of sensory physics, which is the study of how sound, taste, smell, touch, and vision are perceived, and within this larger field, in the subspecialty of psychoacoustics.

Ann Eddins, a specialist in auditory physiology, studies the brain's temporal processing of sound, or how sound varies over milliseconds of time. "There is a lot we don't know about how the auditory system codes time," says Eddins. "Most people are able to process temporal variations in sound, but in hearing loss we think people lose some of this processing ability."

This results in sounds being smeared together, especially if the person is listening in background noise, she says, which probably contributes to poor understanding of speech in the hearing impaired.

Eddins is studying the question of how the temporal aspects of sound are processed in the brain using several approaches, working with an animal model. On a "global" level, she measures the electrical action created by groups of cells in the brain, called evoked potentials, during sound. This identifies the parts of the brain that are activated. She then measures responses of single neurons in the regions activated, to determine which cells respond to sound duration, or high or low frequency.

One of the theories she is following is that during hearing loss, these cells may lose their sensitivity due to lack of stimulation. "This leads us to address a number of questions," she notes: "How plastic is the brain? Are the cells in the brain being damaged? If we can provide some other type of stimulation, can they recover? Can we stimulate them in a way that will help them respond better?"

In yet another approach to studying the temporal quality of sound, Eddins is conducting PET studies on human volunteers to observe which parts of the brain are active when exposed to auditory signals and what features of sound prompt the brain to shift focus from one part to another.

"We are trying to understand why hearing comes easily when listening to certain aspects of sound, while other aspects are more difficult," Eddins says. "We've found that processing shifts from one side of the brain to the other, depending on whether you are listening globally (such as to general conversation) or locally ( as to a teacher's instructions.)"

This work may help to explain why a problem student "can't hear" even though a hearing test finds no deficit: There may be a glitch in the central processing.

David Eddins, Ph.D., trained in clinical audiology and experimental psychology, studies how the intensity of a sound varies across different frequencies, a concept called spectral processing.

"The ability of the ear to identify peaks and valleys of sound is very important in identifying the characteristics of sound," he says. "Every sound has a characteristic spectral pattern, which helps in identifying the source of the sound and in telling the difference between sounds, but we don't know how the brain processes this information."

Eddins bases his research on earlier work of vision researchers. These scientists had shown that the brain breaks down an image into many different parts, assigns the parts to specific places in the brain's visual center, where specialized cells tuned to certain spatial frequencies become exited and create a neural representation of the image.

"This discovery brought a revolution in visual science," Eddins says. "We think there may be a general mechanism for processing features of all stimuli. Are cells in the brain tuned to certain spatial frequencies for hearing? We have found strong evidence of "tuning," and think tuning can be explained by the presence of channels - groups of cells devoted to different spatial frequencies of sound. This provides us with a basic understanding of how sound is interpreted in the brain and how this tuning changes with hearing loss.

"We suspect that the evidence we and others find in this research will completely change the way we think about how the central auditory system works."

Knowledge is power in nearly every endeavor, and this is particularly true in basic scientific research. Understanding how hearing is lost and how it can be recovered or its loss prevented will make possible the development of new devices and therapies that will brighten the lives of millions of people.

The future for understanding and treating hearing loss and other hearing disabilities looks bright, Salvi says. "Drawing from brain imaging, genetics, neuroscience, molecular biology, and biochemistry, we now have a whole arsenal of weapons at our disposal, allowing us to look at acquired hearing loss at the molecular level," he says, "to those that let us look at the whole brain at once."

Great-grandmother with her ear trumpet no doubt would be amazed.