Hearing loss is a common problem, but there is not a singular common cause. Genetics, drug toxicity, trauma, aging and noise exposure are all factors that can contribute to hearing loss. 

For more than two decades, Dr. Mathog has led the department of otolaryngology and maintained its position as a top 20 program in NIH research funding.

"This makes a researcher's job particularly challenging," said Robert Mathog, MD, professor and chair of otolaryngology at the Wayne State University School of Medicine. "There are many parts of the auditory system that can be adversely affected and result in hearing problems, but they are not all linear processes. Our scientists must begin by investigating the cellular structures and mechanisms, and work their way up."

Through his 22 years as department chair, Dr. Mathog has seen science advance and change, but his academic philosophy and mission have remained the same. He says, "I've recruited scientists with the most promising careers, and in almost every case thus far, our efforts have paid off." 

They certainly have paid off handsomely where the National Institutes of Health (NIH) is concerned. Dr. Dennis Drescher received the prestigious Jacob K. Javitz Neuroscience Investigator Award, which is given to only five percent of the researchers funded by the NIH. In addition, four of the five full-time research investigators in the department currently hold NIH grants.

Dr. Mathog realizes, however, that the research must be continued and carried out in clinical arenas too. With a great commitment to education, the department of otolaryngology at the WSU School of Medicine is one of only seven programs in the country with an NIH training grant. That grant has been funded for nearly 15 years, and has allowed medical students, residents, and fellows to learn from and practice with premier scientists.

"This combination of excellence in research and commitment to education is what sets WSU apart," said Dr. Mathog. "Our NIH funding has kept us among the top 20 otolaryngology departments in the nation over the past two decades. In fact, we've been ranked as high as number four in the past, and we expect to sustain our reputation as a top institution for hearing research."

Dennis Drescher, PhD
Professor of otolaryngology and biochemistry
Director of molecular research (in otolaryngology)

Dr. Dennis Drescher says knowledge of the molecular structures in the ear is ultimately sufficient to define hearing function.

Traditionally, the ear has been studied as a mechanical system, and hearing is generally understood in terms of vibrations, sound waves and acoustics. But Dr. Dennis Drescher, a biochemist, looks far beyond the mechanical system.

"Knowledge of the molecular structures in the ear is necessary, and ultimately sufficient to define the function of hearing," said Dr. Drescher. He points to the example of the voltage-gated calcium channel (VGCC), a molecular entity which promotes the release of transmitters, allowing electrical signals to be changed to chemical signals in the inner ear. Since the VGCC is a large protein, Dr. Drescher is able to chart its amino acid sequence to determine three important properties: pharmacological specificity, kinetics and uniqueness of its ion pore.

As a main research focus, Dr. Drescher studies glutamate and other neurotransmitters of the hair cell, which may lead to the development of pharmaceutical therapies that could either decrease the excitatory action of the transmitters to help patients with conditions of presumed over-excitation, such as tinnitus, or to enhance transmitter action to correct problems of deafness and disequilibrium. Secondly, he studies calcium channels that mediate the release of transmitters. The hair-cell VGCC opens and closes very rapidly, with virtually no fatigue. This is not true of other calcium channels, like those of the heart, which can inactivate. The special properties of the inner-ear calcium channels make them potential targets for medications. Finally, molecular biological techniques have allowed Dr. Drescher to trace novel actions of transmitter receptors of the hair cell that modulate transmission of sound signals.

In the 1970s, Dr. Drescher worked at the National Institutes of Health, where he was the first to purify an inner ear enzyme, cochlear carbonic anhydrase. In 1978, Dr. Drescher was appointed to the faculty of the Wayne State University School of Medicine. Since then, he has had continuous funding for his research involving the molecular biology, biochemistry and neurochemistry of hair cell functions, particularly the neurotransmitter systems.

In fact, in studying glutamate, which is thought to be the hair cell's major afferent transmitter or molecule which launches the sound signal from the ear to the auditory nerve and brain, Dr. Drescher has uncovered evidence for other transmitters. He noted that glutamate blockers can not completely inhibit the neural activity of hearing and balance, which meant that something other than glutamate was at work. It turned out that there were additional hair cell transmitters that act at very low concentrations. He and co-principal investigator Dr. Marian Drescher are now working to identify the chemical structures of these unnamed transmitters.

Dr. Drescher's research also addresses the afferent nerves, which receive auditory input, and the efferent nerves, which send signals from the brain to the inner ear to help process sounds. Such signals from the efferent nerves allow the listener to detect where the sound originated and to differentiate between meaningful sound and background noise. One of the efferent transmitters is acetylcholine, and Dr. Drescher is studying a new acetylcholine receptor, called alpha-9, which is used by the auditory and olfactory systems, but is not present elsewhere in the body.

Now in his 20th year of funding, with three major grant projects in progress, Dr. Drescher says, "Although we presently do not have a complete understanding of the structural-functional relations of the cells of the inner ear, we are beginning to assemble accurate information for key molecules, and are thus providing a dependable data base on which to build."


Marian Drescher, PhD
Associate professor of otolaryngology

Dr. Marion Drescher studies adenylyl cyclase in the inner ear.

With a National Institutes of Health grant for more than $700,000, Dr. Marian Drescher is taking on the "nine lives" of the enzyme adenylyl cyclase (AC) in inner ear sensory epithelia. Adenylyl cyclase, which is one mediator of signal transduction in hair cells and their neural contacts, comprises nine isoforms, each characterized by specific pharmacology and tissue localization. For example, various AC isoforms are either activated, insensitive to, or even inhibited by calcium. By studying AC isoform expression at specific sites in the sensory epithelium, information can be obtained about the pharmacology of cAMP-signal transduction at work in each site, thus providing an understanding of AC's role in mechanosensory transduction and neurotransmission.

Stereocilia (cytoplasmic extensions at the top of hair cells) bend during sound stimulation, opening ion channels and permitting mechanosensory transduction. The consequent depolarization allows an influx of calcium at the base of the hair cell, promoting exocytosis of transmitters, including glutamate. Receptors on afferent nerve fibers are activated and the signal is carried to the brain. The hair cell afferent signal is also controlled by efferent nerve fibers originating in the brain. Each of these steps is potentially subject to AC modulation.

Dr. Drescher is trying to determine the mechanisms behind this modulation by identifying the proteins that are phosphorylated in response to cAMP synthesis and protein kinase A (PKA) activation. As an example, hair cell transmission is regulated by efferent neurotransmitters such as dopamine. "Dopamine is important because dopamine agonists can protect against loud sound or glutamate-induced destruction of the afferent nerve fibers." Both pre- and post-synaptic dopaminergic receptors operate through the AC second messenger system and PKA, with specific protein phosphorylation thought to contribute to dopaminergic protection.

Besides PKA-mediated protein phosphorylation, adenylyl cyclase may initiate signal transduction directly through cAMP and cAMP-gated ion channels. "Adaptation" of mechanosensory ion current in the hair cell, occurring over millisecond intervals, appears to be targeted directly by cAMP, raising the possibility of involvement of cAMP-gated ion channels. Dr. Drescher is utilizing molecular biology to determine mRNA expression in the hair cells of these cyclic nucleotide gated ion channels.

Dr. Marian Drescher earned her PhD in biochemistry from the University of Wisconsin in 1974. She came to Wayne State University in 1979 for postdoctoral research in the department of otolaryngology and has since moved through the ranks to associate professor. For 20 years, she has focused on the identification of acoustico-lateralis transmitters, an investigation which is ongoing. 

"An understanding of hair cell mechanosensory transduction and hair cell transmission at the molecular level is integral to rational treatment and eventual prevention of a variety of auditory and vestibular disorders," said Dr. Drescher. 

Paul Finlayson, PhD
Assistant professor of otolaryngology

Dr. Finlayson looks at the role of the central nervous system in hearing loss.

The aging process can produce changes in the central nervous system (CNS), some of which contribute to hearing loss. It is estimated that more than 50 percent of the population over age 60 experiences hearing or auditory problems, and Dr. Finlayson is investigating why.

"We are finding that peripheral hearing loss and central nervous system changes don't have to be simultaneous; however, changes in one can certainly affect the other," said Dr. Finlayson. One target of these changes is the inferior colliculus (IC), which receives sound inputs, and then encodes various properties of the sound, including location, intensity and duration. The IC neurons undergo adaptation and recovery periods, during which nerve firing is reduced. When adaptation occurs in the central nervous system and alters neuron firing, echo suppression may occur. 

Dr. Finlayson explains it this way, "Echo suppression masks sounds due to neuron suppression. So, if you are exposed to sounds followed by another short tone, you won't even hear the second one, because central auditory cells are not responding." In older subjects, IC neurons are suppressed longer, so there is lower firing activity for longer periods of time. 

This type of hearing loss (echo suppression) occurs in the elderly over all frequencies, while normal peripheral hearing loss due to aging and external factors, like prolonged loud noise, occurs at high frequencies. In addition, inhibition of IC neurons may change in old age and also contribute to loss of hearing and speech intelligibility. This leads researchers to believe that this is a CNS-induced deficiency, not a peripheral hearing deficiency.

The ability to localize sound is also important for speech comprehension, said Dr. Finlayson. Humans have a binaural advantage, which means they utilize both ears to make sense of competing sounds from different locations. Sound localization is dependent on binaural processing of interaural disparities in time and intensity. These two primary parts of hearing comprise the basis of his research.

Neurons in the superior olivary complex (SOC), such as the lateral superior olivary nucleus (LSO), encode the differences in the timing and intensity of sound arriving at our ears. These neurons send information to IC neurons. Neurons in the LSO respond to sound stimuli with a precise firing pattern ("chopper response") which can encode the location and onset timing of a sound. 

According to Dr. Finlayson, the pattern of SOC neuron responses may be affected in aging, and contribute to changes seen in the IC. But good news comes from Dr. Finlayson's studies, which provide preliminary evidence that the auditory system can be modulated and adapted.

"It's not surprising that hearing changes are associated with changes in the CNS," said Dr. Finlayson. "After all, the CNS is also responsible for Alzheimer's, memory loss, and other side effects of the aging process. Therefore, it stands to reason that the central auditory system can also be affected by aging."

After working at the University of British Columbia's Rotary Hearing Centre for nearly seven years, Dr. Finlayson, a neurophysiologist, joined the Wayne State University School of Medicine in 1999. His work has been funded by the Deafness Research Foundation and the British Columbia Health Research Foundation.


Margie Crawford, PhD
Assistant professor of otolaryngology

Dr. Crawford is an audiologist who takes a proactive role in helping her patients prevent hearing loss.

Audiologists have traditionally been trained to test people's hearing; but Dr. Margie Crawford feels a greater responsibility to her patients. "I am trying to identify specific populations who are at high risk for hearing loss," she said. "Rather than simply confirm that people have hearing loss, I want to help prevent it and educate those who are most susceptible." 

People with sickle cell disease are one of these at-risk groups. Dr. Crawford, who recently joined Wayne State from the University of Iowa, has conducted studies showing that adults with sickle cell disease are at a significantly increased risk for cochlear and retro-cochlear dysfunction. In fact, the incidence of hearing loss in the general African-American population is about two percent. In patients with sickle cell disease, it is 40 percent.

Sickle cell disease is characterized by life threatening infections, stroke, kidney damage, and intense episodes of pain during which blood flow is restricted and tissues are deprived of oxygen. Now, potential hearing loss can also be added to that list of symptoms, according to evidence collected by Dr. Crawford in studies since 1991.

Sickle cell disease alters red blood cells into rigid, crescent-shaped cells that clog the blood vessels. This obstruction blocks blood flow and causes ischemia in the cochlea and its extensive capillary structure, contributing to the hearing loss. "It's hard to tease out a single cause, since sickle cell disease constitutes a number of complications" said Dr. Crawford. "But there is clearly a link between hearing ability and the loss of oxygen and blood supply to the inner ear."

The next step is to look to the central nervous system and trace contributing pathways there. Dr. Crawford's preliminary studies indicate that sickle cell disease patients display deficiencies in subtle auditory functions such as frequency/tone recognition, speech recognition, and reflex to sound, suggesting that the central auditory system also is affected.

Dr. Crawford and her colleagues also found hearing differences based on severity of the disease. The highest prevalence of hearing loss was in people with HbSC, a form of sickle cell disease. A possible explanation for this finding is that people with HbSC may have more complications involving the brain. 
A major goal of Dr. Crawford's is to make hearing tests part of the regular health routine for at-risk patients. "For sickle cell patients, doctors are very busy treating the body, trying to control the patient's pain, testing the kidney function, and concentrating on more life-threatening things," she said. "But hearing loss is an important issue that shouldn't be ignored."

Studies are currently underway through WSU's otolaryngology clinic at the University Health Center to screen sickle cell patients for hearing loss and to follow them through the course of disease progression. One goal is to look for links between particular drug toxicities as a contributing factor to hearing loss.

Another will test children with sickle cell disease to see if they follow the same patterns as adults. Still another will look specifically at penicillin to see if it protects against hearing problems. "We need to pay attention to any factors that may place people at risk," Dr. Crawford said. 

James Kaltenbach, PhD
Associate professor of otolaryngology

Dr. Kaltenbach is developing therapeutic treatments for tinnitus.

In 1995, Dr. Kaltenbach joined the department of otolaryngology and things have never been better. With substantial funding from the National Institutes of Health, five new research projects underway, and some possible therapeutic treatments for tinnitus, Dr. Kaltenbach is excited to see the rewards of his research labor.

For more than 10 years, Dr. Kaltenbach had been studying tinnitus, the ringing sensation that affects millions of Americans after intense sound exposure, certain drug treatments, or injuries to the ears. Using rodent models, his laboratory has provided evidence that the cochlear nucleus is critically involved.

His laboratory group has been able to show physiological evidence of neural hyperactivity in the cochlear nucleus of hamsters and rats after intense sound exposure. It is known from studies in other laboratories that animals develop tinnitus after exposure to the same sounds that cause hyperactivity in the cochlear nuclei. Currently, Dr. Kaltenbach is trying to determine the relationship that hyperactivity in the cochlear nucleus has to tinnitus.

In order to determine the nature of the sound heard by the animals and to determine if the ringing is similar to that heard by humans, Dr. Kaltenbach will try to match the locus of peak neural activity in the cochlear nucleus to the pitch of the tinnitus. Since certain tones are processed in certain parts of the cochlear nucleus, he can better understand what animals hear based on where the abnormal activity occurs in the cochlear nucleus.

His laboratory is using an immunohistochemical probe to label the cells which become hyperactive after sound exposure. Preliminary evidence shows that the hyperactive cells are located in the deepest part of the dorsal cochlear nucleus. The identification of the class of cells with abnormal activity will provide insights into the mechanisms underlying tinnitus.

Dr. Kaltenbach also is studying the chemical pathways involved in the generation of hyperactivity. This information is needed to guide the development of therapeutic drugs for the treatment of tinnitus. Drugs that decrease neural activity in targeted areas may be able to provide relief from the continuous ringing that can be very bothersome to tinnitus-sufferers. Agonists of the amino acid, GABA, have already been used in their animal model to inhibit neural activity in the cochlear nucleus. Pfizer and other pharmaceutical companies are currently investing in this line of research raising the hope that drug therapies may be on the horizon in the foreseeable future. To date, the only tinnitus treatments available are counseling and psychotherapy.