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Can we make the ringing stop?

Can we make the ringing stop?

Illustration: Glynis Sweeny
"I remember waking up on the morning of April 12, 1994, with a high-pitched squealing in my ears," says a 56-year-old Buffalo businessman. "I thought it was the microwave going off downstairs, but I wasn't able to find the sound anywhere. Ultimately, I went into a state of depression and couldn't even work. I have spent the last four years looking for help, but I have been told this is something I'll have to learn to live with because there is no known treatment."

His problem is tinnitus, the false perception of sound in the absence of an external stimulus. More commonly known as ringing in the ears, tinnitus actually encompasses a wide range of symptoms, including buzzing, roaring, whistling, hissing, high-pitched screeching, or other sounds, according to the American Tinnitus Association. Many people experience occasional episodes of transient tinnitus – a few moments of screeching or squealing in the head that stops as suddenly as it starts. But about 15 million Americans (including 10 percent of all elderly Americans) suffer from tinnitus that never stops. In rare cases the affliction can be so maddening that it drives its victims to suicide.


Alan Lockwood (left) and Richard Salvi at the Center for Positron Emission Tomography.

(Click to view larger image.)
Photo: KC Kratt

Until this year, the source of the phantom noise was unknown. Did it originate in a defect in the inner ear (the more widely accepted conjecture)? Or could it be an entirely cerebral phenomenon?

Now two UB researchers, Alan Lockwood, M.D., a neurologist, and Richard Salvi, Ph.D., a specialist in the physiology of hearing, have solved that mystery. Their findings, published in the January 1998 issue of the journal Neurology, are likely to revolutionize work in the field.

The story of their discovery is one of coincidence, serendipity, good science – and a little help from UB.

In the early 1990s, UB and the Buffalo VA medical center, which is located across Bailey Avenue from the university's South Campus, began construction of a jointly operated positron emission tomography (PET) facility. Positron emission tomography is a method of looking at the actual functioning of organs in the living body. It works by tracking a benign form of positron-emitting radioactive material introduced into a subject's bloodstream; positron-sensitive cameras record changes in blood flow in the organ in question. PET scans, as these observations are called, have now become a relatively commonplace – albeit expensive – diagnostic tool.

The radioactive material used in PET studies has a half-life measured in minutes (by comparison, the half-life of radioactive materials used in nuclear power plants is thousands of years). Part of the UB-VA project was to build a cyclotron on the UB campus for the production of the required radioactive markers, as well as a tunnel for moving the material quickly from the cyclotron to the PET facility at the VA.

The cyclotron was to be located in the basement of Parker Hall, directly below UB's Center for Hearing and Deafness. Center codirector Richard Salvi called Alan Lockwood, who was in charge of the PET project, to discuss his concerns about what noise from the construction site might do to some delicate sound-controlled experiments he was running upstairs. Before long, their conversations broadened from construction schedules to tinnitus, a long-standing interest of Salvi's. Lockwood was looking to recruit interdisciplinary research projects for the new PET facility. From this chance meeting developed what has now – several years later – become the PET center's largest research project.

Dick Salvi has been working on tinnitus since he was a graduate student at Syracuse University in 1975. He always expected to find its origins in aberrant neuronal activity in the inner ear where the hair cells of the cochlea (the chamber of the ear that processes sound waves into the nerve impulses that carry information to the part of the brain that "hears") were somehow sending false signals, he says. But he didn't find what he was looking for.

He has spent much of his professional career working on the physiology of the inner ear. His laboratory was one of the first to demonstrate that some species – in this case, chickens – can regrow damaged hair cells (humans can't, and damaged hair cells in the inner ear are a leading cause of deafness).

About 10 years ago Salvi began to think that the elusive origin of tinnitus was, in fact, in the brain itself. He based this on evidence from animal studies showing that peripheral hearing loss induced by drugs or loud noises causes the brain to become, in Salvi's words, "hyperactive, or almost more sensitive." In addition, work done elsewhere on other senses was beginning to suggest that changes in those senses' perceptual organs can lead to some central nervous system reorganization, perhaps even to anatomical changes in the brain.

With PET scans offering a window into brain function, Lockwood and Salvi four years ago began preliminary work on an experimental look at the brain function of persons with tinnitus.

To locate persons with tinnitus who might be willing to participate in the study, Salvi contacted a local tinnitus support group. The group advertised that Salvi would be discussing a tinnitus research project at their next meeting.

"There were 70 or 80 people at the meeting," Salvi says, recalling how surprised he was by the turnout. But what he heard that night provided an even bigger surprise – and proved to be the key to the experimental work that followed.

"One person in attendance said he could regulate his tinnitus by clenching his teeth." Salvi hadn't known this was possible. "Then three other people reported the same ability to make their tinnitus louder or quieter by pressing or touching their face, or pressing a tooth, or sucking back on the tongue. What they said provided a breakthrough in the way the experiment was designed because it meant we could look at the brain in two different states: when the tinnitus was at its normal level, and when it was louder or quieter."

Salvi recruited all four persons to participate in the experiment.

Experimental design is critical," Lockwood says, citing the fundamental rule of empiricism. "Without a well-designed experiment, you don't get good data."

A PET scan of the brain can show changes in blood flow; in simple terms, increased blood flow in a particular region suggests that something is happening there. When PET scans are associated with a mental operation, the resulting data can shed light on how the brain works. For example, in another study conducted at the UB-VA PET center, when subjects' brains were scanned while they formed the past tense of a series of regular verbs (row, rowed) and irregular verbs (run, ran), blood flow increased in different places in the brain depending on which kind of verb each subject was conjugating. This suggests that the two kinds of past-tense formation are actually two different mental tasks. The researchers hypothesize that one is the application of a rule – add "-ed" to all regular verbs – and the other is memory-based.

The PET scan says nothing about how this mental work is accomplished, or even where, necessarily, it is happening (is the increased blood flow evidence that mental work is being done at that spot or, rather, coordinated from that spot?). But this much can be safely said: If, for a statistically valid number of subjects, forming regular verb endings increases blood flow in one place while forming irregular verb endings increases blood flow in a different place, then they are different mental operations.

For their tinnitus experiment, Lockwood and Salvi did six brain scans of each of the four subjects who could modulate their tinnitus: three scans while they were at rest, and three scans while they did what Lockwood refers to as their "trick" or, more formally, their "oral facial movement." With PET scans of the six control subjects performing the same oral facial movements, Lockwood could subtract the brain activity caused by that action from the scans of the subjects with tinnitus. Then, by comparing scans of the modulated tinnitus (minus the brain activity directly related to the jaw-clenching) with scans of the regular tinnitus, Lockwood says, "we were able to localize the spontaneous neural activity associated with tinnitus to the temporal lobe of the brain, which is also the brain's most important auditory region."

In other words, the researchers now knew where in the brain to look for tinnitus-related activity, whatever its cause.

But was this neural activity a response to something happening in the subjects' ears, or was it something with no external origin at all? To answer this question, Lockwood and Salvi looked at what happened when their tinnitus subjects heard real sounds. For this part of the experiment, they used subjects who reported "hearing" their tinnitus in only one ear; the subjects were scanned as they listened to a tone through headphones. Lockwood and Salvi were thus able to compare brain activity associated with real sound with brain activity associated with tinnitus.

"What we found was that real sounds caused bilateral neural activity [neural activity on both sides of the brain], whereas the phantom sounds of tinnitus were associated with unilateral activity [activity on only one side]," Salvi says. "This told us several important things, the most significant of which is that the source of this neural activity had to be in the brain itself. The unilateral delivery of sound to just one ear activates only one cochlea [inner ear]. And if just one cochlea had been the site of the spontaneous neural activity that causes tinnitus, we would have seen bilateral activation, just as we saw when we played real sounds. So this comparison between phantom sounds and real sounds enabled us to arrive at our second major finding, which was to localize the source of the phantom sounds to the brain, instead of to the cochlea, where many investigators have long believed that tinnitus was originating."

This finding is more than just interesting to neurologists: If tinnitus is ever to be treated, it is obviously necessary to know where it does and – more importantly – does not originate. The brain, not the ear, now appears to be the place to start.

"One person in attendance said he could regulate his tinnitus by clenching his teeth." Salvi hadn't known this was possible.

Lockwood and Salvi made two other intriguing findings in the course of their experiment. When they looked at the neural activation caused by real sound both in subjects with tinnitus and in control subjects without tinnitus, they observed that the tinnitus subjects – all of whom also had some hearing impairment – showed neural activity over a much larger area in the auditory cortex. This confirmed physiological work that Salvi had done previously that suggested that the part of the brain that processes high-frequency sounds does not become inactive when the ear loses its ability to hear high frequencies; rather, it "rewires" itself and is activated by lower-frequency sounds.

"This finding indicates that the circuitry of the auditory system has been changed in some way in the subjects with tinnitus," Salvi observes. "We think that's important because we surmise that some of these new connections are the ones responsible for causing the phantom-sound sensations."

Quite unexpectedly, the UB team also observed a connection between the auditory cortex in tinnitus subjects and the hippocampus portion of their limbic systems (the part of the brain that, among other things, regulates emotion).

"In tinnitus patients, but not in normal controls, there is a crossover between the auditory system and the limbic system," Lockwood says. About one-third of the people with tinnitus report severe to crippling emotional or psychological effects from the condition. Lockwood speculates that there is something intrinsic in the brain that separates the tinnitus "listener" from the tinnitus sufferer.

Is some palliation or an outright cure for tinnitus around the corner? A news release from the American Tinnitus Association sums up the implications of the discoveries this way: "As encouraging as the news is, tinnitus patients are cautioned that a cure is not on the immediate horizon, nor is a specific treatment regimen."

But research is now headed in the right direction. "By identifying the sites in the brain that mediate tinnitus, we have taken a critical step down the road toward a cure for this disabling condition," Lockwood says.

And the next steps down that road, at least at UB, will be funded by a $1.3 million National Institutes of Health grant announced at the end of 1997. The grant represents a 75-fold return on UB's $20,000 investment in the work when it was no more than an idea.

Once they knew how they wanted to use PET technology to investigate tinnitus, Salvi and Lockwood applied to UB's Multidisciplinary Pilot Project Program for $20,000 in seed money to get their research started. Those funds moved the work along to the point where the American Tinnitus Association granted them $46,000 to continue it. The discoveries Lockwood and Salvi then made were the basis for the major NIH grant.

"We had a great idea and no data," Lockwood says. "We used the seed money from UB to get enough data to allow us to make a proposal to the American Tinnitus Association. It was the seed money that really got the whole thing off the ground."

Judson Mead is editorial manager for the UB Office of Publications.

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