19 January 2011—Scientists say they can cure tinnitus—persistent ringing in the ears—by pairing certain tones with stimulation of a nerve in the neck.
Tinnitus is caused by noise damage to the sensory cells in the inner ear, or cochlea. This damage results in changes to the organization of the brain’s auditory cortex, a region that contains a "frequency map" of sounds. Damage to the inner ear causes a portion of this map to take over other parts of the cortex, causing the ringing.
"The pathology is in the brain, not in the ear," says Navzer Engineer, vice president of preclinical affairs at MicroTransponder, a medical-device start-up firm that collaborated with scientists at the University of Texas at Dallas on the research reported last week in Nature.
The Texas scientists reasoned from earlier studies that they could affect the brain reorganization and perhaps undo it. Earlier work involved pairing audible tones with stimulation of structures deep in the brain. But those structures aren’t easily accessed, so the researchers looked for another way in. They found it in the vagus nerve, a bundle of fibers that runs down the neck and innervates organs in the chest and abdomen. Medical-device makers and researchers have used the vagus nerve as a port into the brain to lessen epilepsy and severe depression. Conveniently, the vagus nerve also projects into brain structures that release neurochemicals in the auditory cortex.
Before trying to fix the brain, the researchers first showed they could mess it up. In experiments with rats, they paired vagus-nerve stimulation with a 9-kilohertz tone hundreds of times per day for 20 days. That had the effect of boosting the number of auditory cortex neurons that responded to the tone by 79 percent, a similar change to what you might expect from tinnitus.
In a separate group of rats they demonstrated the treatment. The scientists showed that they could repair the tinnitus damage by pairing vagus-nerve stimulation with tones that were outside the tinnitus frequency. This basically had the effect of squeezing the number of neurons that responded to the tinnitus frequency back down toward a normal number.
The experiments themselves needed a clever design, because the researchers couldn’t ask the rats if they heard ringing in their ears. So the scientists had to use other methods, such as assessing the rats’ behavior and probing their brains with arrays of microelectrodes.
White noise similar to that used in experiment.
White noise with a 50 millisecond gap, similar to the "startle cue" in the experiment.
First the researchers measured the rats’ "cued-startle response." The rats hung out in a cage amid a constant hum of white noise [audio clip at right]. The scientists would periodically put a 50 millisecond gap in the noise [audio clip at right] immediately before a very loud white noise, which would startle the rats. After some training, the rats came to expect the loud sound after the deletion, so they weren’t quite as startled by it.
Once this behavior was established, the researchers blasted the rats, under anesthesia, with a deafening tone. They could tell that it led to tinnitus because the rats stopped responding to the gap that precedes the startling sound. Basically, the rats jumped higher when they heard the loud noise, because they could no longer tell when it was coming. Their tinnitus was producing a hum that filled in the gap. After the vagus-nerve stimulation therapy, the researchers could tell the tinnitus was gone when the rats started responding to the warning cue again. They also measured the corresponding reorganization and reversal in the rats’ auditory cortex using implanted microelectrodes.
MicroTransponder has begun human trials of the therapy in Belgium, according to its CEO, Will Rosellini. The company has met with U.S. medical-device regulators at the Food and Drug Administration to map out the device’s approval process, but Rosellini warns that the process is likely to take years—and cost millions of dollars. In 2010, MicroTransponder raised US $7 million from venture capital sources and $4.3 million from government sources. Of that, $1.7 million came from the National Institute on Deafness and Other Communication Disorders, part of the U.S. National Institutes of Health (NIH).
"Tinnitus isn’t as big a problem as other neurological problems, so venture capital has ignored it," says Rosellini, who is also a graduate student in neuroscience at the University of Texas at Dallas. "NIH has stepped in to fill that gap."
MicroTransponder was initially formed to tackle the problem of chronic pain, a $2 billion market served by, among other treatments, implanted pacemaker-like stimulators. "The big problem is that the wire breaks or an electrode moves," says Rosellini. MicroTransponder calls its solution the SAINT (Subcutaneous Array of Implantable Neural Transponders) system, an implanted wireless electrode affixed to the nerve causing the pain. The electrode gets its power through an inductive coupling with a coil outside the body. But the company’s real innovation, he says, is that it came up with an electrode design that stimulates nerves using a small percentage of the energy required by other designs. Besides chronic pain and tinnitus, MicroTransponder is exploring the wireless stimulator’s use in treating urinary incontinence and post-traumatic stress disorder.
Engineer says that there is some similarity between the way tinnitus reorganizes the brain and the way certain types of chronic pain change neural circuits in the brain and spinal cord. So the researchers hope to exploit some of their tinnitus findings in pain treatment as well.