© MARI SCHMITT/SCIENCE SOURCE; © ENCYCLOPEDIA BRITANNICA/UIG/GETTY IMAGESIt often starts off with a bang. Many a soldier, construction worker, concertgoer, or innocent passerby exposed to a loud noise walks away with the telltale symptom of tinnitus, a persistent ringing in the ears. The condition can also arise from other ear traumas, such as middle-ear infections or exposure to high pressure while scuba diving, and begins with damage to the hair cells in the cochlea of the inner ear or to the auditory nerve. Until recently, such damage was thought to be the cause of the phantom sounds that plague tinnitus sufferers. Now, researchers are realizing that it’s much more complex than that.
“Damage to hair cells and auditory nerve fibers sets the stage for the development of tinnitus,” says Jennifer Melcher of the Massachusetts Eye and Ear Infirmary. But the true culprit is really the brain, which eventually begins to compensate for the loss of input from the ear by “turning up the volume” on the sound signals it is trying to pick up, she adds. Navzer Engineer, chief scientific officer of Dallas-based MicroTransponder, which is developing a neurostimulative treatment for tinnitus, agrees: “Cells in the brain don’t stay dormant” even though they have lost input from the ear, he says.
It’s unclear when the condition transitions from the ear to the brain. Researchers also do not yet know whether the brain or peripheral nerves are primarily responsible for amplifying the spontaneous neural activity in the auditory pathway. But in the end the effect is the same: the brain begins to capture sounds of its own creation. “The pathology is in the ear . . . but the sounds are generated by the brain,” says Engineer.
The University of Regensburg’s Berthold Langguth, chairman of the executive committee of the Tinnitus Research Initiative, likens the compensatory sound to the phantom limb sensation experienced by amputees. And like the phenomenon of phantom limbs, there’s not just a single brain region at fault. In addition to the auditory cortex, the limbic cortex—particularly the amygdala, the brain’s emotional center—as well as the temporal, parietal, and sensorimotor cortex areas have all been implicated in tinnitus perception (Curr Biol, 25:1208-14, 2015; eLife, 4:e06576, 2015).
A better scientific understanding of tinnitus could be key to developing an effective treatment. One in five Americans has tinnitus, including more than a million veterans who experienced loud noises in the line of duty, and many suffer a severe form of the disorder. Yet treatment options are largely limited to cognitive behavioral therapy to learn to tune out the sound and physical exercises such as contracting the head and neck muscles (by clenching their jaw, for example) to adjust the rogue sound’s pitch or loudness. For those who continue to suffer significant psychological and emotional consequences of tinnitus, there has been no pharmaceutical treatment or cure. “It’s a very desperate group,” Engineer says.
Inside the ear
The most advanced treatment in development for tinnitus targets the auditory neurons that connect the hair cells of the inner ear to the auditory cortex. In the mid-1990s, researchers at Inserm in Montpellier, France, found that chemically inducing tinnitus in rats was associated with upregulated N-methyl-D-aspartate (NMDA) receptors on the animals’ cochlear neurons (J Neurosci, 23:3944-52, 2003). NMDA receptors play a role in forming new synapses at these neurons, and regulate the levels of other neuronal receptors. In 2003, teaming up with Swiss entrepreneur Thomas Meyer and his company Auris Medical, the Inserm researchers also observed such increased levels of NMDA receptors in rodents suffering from noise-induced tinnitus. Prior to noise trauma, the animals had been trained to jump onto a pole in response to a sound, and after trauma, rodents with tinnitus continued these behaviors, even in the absence of an external tone.
To treat the condition, the group set about designing a drug that would block NMDA receptors. These days, Auris is testing the small-molecule drug S-ketamine in two Phase 3 trials of trauma-induced tinnitus patients. The treatment, delivered directly into the inner ear via three injections over three days, must catch the disorder while the problem is still within the ear, before the brain has begun overcompensating for the loss of hearing. Once that happens, no amount of adjustment to the receptors on the auditory nerves will do any good.
Because it is not known when that transition from ear to brain occurs, one of the current trials, of 300 European patients, is specifically testing tinnitus sufferers who have developed the condition no more than three months prior to treatment. The other, a study of 330 North American patients, is investigating a therapy within one year post-trauma. Preliminary results suggest that S-ketamine is effective beyond three months, but declines in effectiveness within a year of the initial trauma, so later stages of the trial are being refocused on the four- to six-month time frame. The trials will be completed at the end of this year, and Auris hopes to submit to the US Food and Drug Administration (FDA) for approval in the summer of 2016.
“[The hope is] that this might show benefits and might become the first drug to be approved for the treatment of tinnitus,” says Langguth, who is not affiliated with Auris. Because the therapeutic is delivered directly into the ear, he thinks that it will be particularly useful for patients who also suffer from hearing loss, an extremely common comorbidity of tinnitus.
S-ketamine will probably not work for all tinnitus sufferers, however, says Meyer. “We feel it’s important to get started and then see what else can be done with this.”
Chemically modifying neurons
Meanwhile, other researchers are developing therapies that target the brain to treat patients whose tinnitus has progressed to the auditory cortex. One strategy currently under investigation is the manipulation of the potassium channels found throughout the auditory pathway. “[Using] potassium channel modulators, the activity in the central auditory pathway can be changed,” Langguth says.
In tinnitus, the auditory maps in the brain rewire themselves without external stimulation.
U.K.-based Autifony Therapeutics began in 2011 as an outgrowth of GlaxoSmithKline’s investigation of potassium channels in the auditory system. Autifony CEO Charles Large and his colleague Giuseppe Alvaro are focusing on the development of the previously unexamined Kv3 potassium channels, which exist throughout the brain and in high abundance on the auditory nerve and cortex, allowing the neurons to signal rapidly. After exposure to loud noises, these channels can be damaged and fail to properly conduct ions, making them an ideal drug target for the treatment of tinnitus.
Working with academic collaborators, Autifony researchers developed a small-molecule drug that enhances the function of the Kv3 channels. In rodent models, the drug reduced the spontaneous neural activity in the midbrain auditory system associated with tinnitus. “We’re dampening down a spurious activity that is believed to give rise to the phantom perception,” says Large. “We have a lot of confidence from our preclinical work that we should see some interesting effects in people with tinnitus.”
Autifony researchers are currently recruiting patients for Phase 2 trials in the U.K. In contrast to Auris Medical’s target patient population, Autifony focuses on people whose tinnitus is established in the brain and who have had the disorder for at least six months (but no more than 18 months). The treatment is currently taken as a daily oral pill for 28 days, although the length of the treatment course is still under investigation.
“Autifony is really quite unique in having a drug treatment that’s been rationally designed around the idea that we can dampen down the hyperexcitability that we see in the nervous system,” Large says.
Retraining the brain
For patients with chronic tinnitus beyond the 18-month window being targeted by Autifony, a third potential treatment is making its way through clinical trials. MicroTransponder’s therapy is a riff on a decades-old treatment for epilepsy and depression called vagus-nerve stimulation. More than 90,000 patients have undergone such treatment.
MicroTransponder was started out of Michael Kilgard’s lab at the University of Texas, Dallas, where Engineer conducted his postdoctoral research. In 1998, Kilgard’s group published a rat study demonstrating that direct stimulation of the nucleus basalis of the forebrain could be paired with the playing of a particular tone to change how sounds map to the brain’s auditory cortex (Science, 279:1714-18). The researchers were later able to accomplish the same sound remapping in the rat brain by stimulating the more-accessible vagus nerve, which projects to the nucleus basalis (Nature, 470:101-04, 2011).
The auditory maps in the brains of tinnitus sufferers rewire themselves without external stimulation. In the human inner ear, the cochlea contains more than 3,500 inner hair cells, each of which is tuned to a single frequency. As these cells are damaged by loud noise, infection, or other insults, the brain is deprived of normal input from the ear at particular frequencies. As a result, neurons that represent adjacent frequencies expand their range to include the missing frequencies. These neighboring neurons begin to fire spontaneously, sending phantom signals to create the perceived sound of tinnitus. Kilgard’s work suggests that retraining the auditory cortex by pairing tones with electrical stimulation could correct such abnormal firing. “There was the idea that maybe there could be specific forms of auditory stimulation which could have a beneficial effect,” Langguth says.
Engineer’s stimulation therapy has successfully stemmed tinnitus in a rat model, in which the animals were exposed to a loud noise that impaired their hearing. The treatment, now in human trials, involves two incisions in the neck and chest wall to insert a helical electrode, which winds around the left vagus nerve in the neck, and wires to connect the electrode to a pacemaker-like pulse generator in the chest. The researchers determine the pitch of a patient’s tinnitus by playing various tones until the patient reports a match with the perceived sound, then pair tones near but not at the tinnitus pitch with vagus-nerve stimulation in half-second pulses. The idea is to train the brain regions that have begun to fire spontaneously—and cause tinnitus—to respond only to the non-tinnitus frequencies that the ear actually hears. “[It] actually reverts the auditory cortex map down to normal,” Engineer says. Vagus-nerve stimulation or the tones by themselves don’t work, he noted. “The key is the pairing.” The course of treatment is a 2.5-hour daily listening session for six weeks.
In a preliminary 10-patient study in Belgium, about half of patients with chronic tinnitus improved (Neuromodulation, 17:170-79, 2014). However, the researchers noted decreased efficacy if the patients were on antidepressants. Stimulating the vagus nerve causes the release of the neurotransmitters norepinephrine and acetylcholine. Antidepressant medications can interfere with this release, suggesting that these natural chemicals are required for the vagus-nerve stimulation treatment for tinnitus to work. The proof-of-concept trial was followed up by a larger-scale study of 30 patients at four sites in the U.S. that concluded this April. The most common side effect was a hoarse voice, but otherwise the treatment is considered safe. Results from the trial will be published this autumn, but Engineer says that the data look promising.
While there is still no approved drug to treat tinnitus, Meyer of Auris Medical is optimistic that the future for patients suffering from the disorder is bright. “We have learned a tremendous amount over the last few years. We know things we absolutely had no idea about 10 years ago,” he says. In addition to the therapies currently in trials for acute tinnitus, “I believe that long-term there will be also solutions for chronic tinnitus,” he adds.
Meanwhile, further research into the pathophysiology of the disease will be critical to develop targeted treatments. “There’s not one tinnitus,” Langguth says. “There are probably many forms, which differ in their mechanisms and differ in their best possible treatment.” Studies that help scientists better delineate these different forms of tinnitus into clinically meaningful subgroups will likely inform future drug targets, he adds.
“The hearing space is where ophthalmology was 10 or 12 years ago,” says Autifony executive Barbara Domayne-Hayman. At that time, the basic research community was not that interested in certain eye disorders, “whereas now it’s an extremely hot and active space. We think that hearing is going to go in exactly the same way,” she adds.