Tinnitus Not Just In Your Ears

by Carl Sherman

April 4, 2011

Tinnitus is noise you can’t turn off. Ringing, hissing, even screaming in the ear is a relentless annoyance—and for some, it’s maddening.

The problem affects an estimated 40 million Americans, and counting. Typically more common in older people, it is turning up with alarming frequency among veterans back from Iraq and Afghanistan and teenagers who may have used their iPods unwisely.

Conventional treatments don’t help much. White noise to mask tinnitus, behavioral training to desensitize patients to it, even extreme remedies like severing the cochleal nerve leave most sufferers still suffering.

That’s because the ringing isn’t in the ear at all. It’s in the brain.

“Attempts to understand tinnitus were initially the domain of otolaryngologists, who treat hearing problems medically and surgically. From that perspective, there wasn’t much to be done,” says Anthony T. Cacace, professor of communication sciences and disorders and otolaryngology at Wayne State University, and chair of the scientific advisory committee of the American Tinnitus Association. “But in the last decade, advances in the study of brain function have put tinnitus in the context of issues that neuroscientists deal with.”

Jennifer Melcher, a neuroscientist at Harvard University and Massachusetts Eye and Ear Infirmary, agrees. “There has been a mind shift away from the ear and toward the brain,” she says. “The growing view is that something in the periphery ”—damage to the delicate hearing apparatus that picks up sounds and transmutes them into nerve signals—“gets tinnitus started. But ultimately there’s a kind of synergy between the periphery, the central auditory system, and non-auditory brain centers, all working together to conspire in the development of tinnitus.”

Brain imaging and electrophysiological measurements suggest that hearing loss—sometimes too small, perhaps, for detection by conventional audiology—leads the auditory cortex to reorganize in an attempt to compensate, which in turn produces hyperactivity that is experienced as constant noise in the absence of external stimulation, much like phantom limb sensations or chronic pain.

A tinnitus network

Most brain research has focused on the auditory cortex. But Josef P. Rauschecker, professor of physiology and biophysics at Georgetown University, believes that while dysfunction there is necessary, it isn’t sufficient. “Not everyone with hearing loss gets tinnitus—just one-third. And when people have tinnitus, it’s not constant. It can be modulated by things like mood and stress.”

In an article in the June 24, 2010, Neuron, he proposed a process that involves the limbic system as well as auditory circuits. One function of the limbic system, he points out, is to evaluate signals from other brain regions, amplifying what’s important and tuning out what’s unnecessary before they reach consciousness. In tinnitus, this “noise-cancellation” filter fails.

A study from his laboratory, reported in the Jan. 13 issue of the same journal, gives support to this theory. Using fMRI, the researchers compared  brain activity in 11 people with tinnitus and 11 controls while they listened to varied tones. The most striking difference was hyperactivity in the nucleus accumbens—a part of the limbic system—in response to tones that matched each patient’s tinnitus.

“There was almost complete separation in activity levels between patients and controls. It’s  rare to see such a highly significant effect,” Rauschecker said. The researchers found anatomical changes in another part of the limbic system: a reduction of gray matter in the ventromedial prefrontal cortex of patients, compared with controls.

Tinnitus-matched frequencies also elicited hyperactivity in the primary auditory cortex of the patients, which correlated with limbic system changes.

“It’s a very nice approach,” says Melcher. “It hits on a theme not just in tinnitus, but in auditory neuroscience in general, that the auditory system isn’t acting alone but is connected to, influenced by, and influencing other areas. The idea is extremely interesting and the first data is in favor of it, but there’s still a lot to do.”

The role of the emotion-regulating limbic system is complex, she says. Depression and insomnia are common among people with tinnitus, and the noise apparently worsens under stress: does this reflect a general state of limbic dysfunction, as Rauschecker suggests, or are the psychological symptoms due to tinnitus?

“It’s a chicken/egg phenomenon, and difficult to sort out,” Melcher says. “One could imagine the link between the auditory cortex and areas mediating emotion as the basis for a vicious cycle—tinnitus causes stress, and the stress make tinnitus worse.”

  Rauschecker thinks limbic system involvement in tinnitus might suggest new types of therapy, such as drugs that target the neurotransmitter serotonin. “Antidepressants have been used in the past, with mixed success, and it may be worth taking this up with more selective agents, perhaps tailor-made for the purpose.”

 The nucleus accumbens, he says, might also provide a new target for brain stimulation therapy, a method of growing interest among tinnitus researchers.

Stimulating solutions

In recent years, the possibility of treating tinnitus with transcranial magnetic stimulation (TMS), and deep brain stimulation (DBS)—treatments already approved for conditions like depression,  epilepsy, and Parkinson’s disease—has attracted increasing attention. “In Europe, they’re also exploring cortical electrical stimulation, implanting  electrodes on the surface of the skull,” says Cacace. “The idea of these approaches is to suppress tinnitus by reducing transmission in the auditory cortex.”

Researchers  at University of Texas in Dallas have another idea. Michael P. Kilgard, principal investigator at the University’s Cortical Plasticity Laboratory, proposes that vagus nerve stimulation (VNS), a treatment also approved for depression and epilepsy, can “retrain” areas of the auditory cortex to normalize aberrant signaling responsible for tinnitus.

In a paper posted on the Jan. 12 online edition of Nature, Kilgard , lead author Navzer Engineer and colleagues reported using VNS to eliminate the behavioral signs of tinnitus in rats that had   developed a version of the disorder.

For VNS, an electrode implanted in the neck sends brief electrical impulses, via the vagus nerve, up to the brain. Among the areas stimulated, says Kilgard, is the nucleus basalis, which releases a host of chemicals—acetylcholine and brain-derived neurotrophic factor among them—that promote neuroplasticity.

The investigators exposed rats to noise to induce hearing loss, then identified those that developed tinnitus using “gap detection.” “The idea is to see if rats can detect brief bits of silence,” says Kilgard. They conditioned rats to respond to a pause in a continuous tone. Rats whose tinnitus filled in the silence could not be conditioned.

Besides the behavioral change, researchers found abnormal activity in the auditory cortex of these rats.

Then they treated the rats with VNS while exposing them to a broad array of tones that excluded the tinnitus frequency, to induce neuroplasticity that would reverse the changes that produced the noise. “We wanted response to that one tone to shrink,” says Kilgard.

After 18 days of VNS, the treated rats no longer displayed behavioral abnormalities suggesting tinnitus, while those given sham treatment still did. Auditory cortex activity was also normalized in the treated rats. “We followed some animals for several months, and saw no signs of returning tinnitus,” Kilgard says.

[Engineer is a full-time employee of MicroTransponder Inc. of Austin, Texas, which develops therapies using neurostimulation. Kilgard is a consultant and shareholder of MicroTransponder Inc.]

The results “are intriguing and provocative, and worth pursuing,” says Cacace, “but I wouldn’t jump into a human trial based on one study.” For one thing, “it’s not clear to me that you can reverse plastic changes, secondary to hearing loss and tinnitus, that were in place for a long time.” [In the rats, he notes, tinnitus had been induced shortly before treatment.]

More generally, Melcher counsels realistic enthusiasm. “These are both really cool papers that get people thinking in new directions,” she says. “But if you look at the history of tinnitus research, there have been a lot of results that others weren’t able to get. It may be that tinnitus is a phenomenon with heterogeneous underlying pathology.

“I’ve tripped up myself, and I know you need to be cautious,” Melcher says. “There are a lot of very desperate people out there, and you have to keep a level-headed view.”