Reclaiming the Sound of Silence

Note: This post is a modified version of an article that I submitted to the Access to Understanding science writing competition sponsored by Europe PubMed Central, which required writing a summary of a science journal article chosen from a short list. So this post may seem different from usual—more narrowly focused and formally written—though I’ve edited it to fit the style of my blog.

 

At some point in your life, you’ve probably experienced that sensation of having a ringing in your ears. Maybe it was after leaving a blaring rock concert or a sports stadium packed with screaming fans.

This sensation is called tinnitus, and nearly every one of us has experienced it at some point. However, some people, up to 10-15% of the population, experience it chronically.1 Tinnitus is most commonly associated with hearing loss induced by excessive noise. This noise damage can accumulate over time or can result from a single incident, such as an explosion. In the U.S., tinnitus is the most prevalent service-related disability reported among veterans—even more common than PTSD.

Imagine how disruptive it would be to hear a constant ringing sound when you’re trying to concentrate or fall asleep. Many people afflicted with tinnitus learn to cope, but 10-20% of patients (1-2% of all people) report serious disruptions in their lives.1 There is no known cure.

Brains gone wild

Tinnitus is a compelling topic of study not only for its impact on human health, but also because it represents a bit of a neurobiological mystery. Hearing is mediated by tiny cells in your ear that detect sound vibrations and transmit those signals to the hearing (or “auditory”) areas of your brain. Excessive noise damages or kills some of those ear cells. So you’d think that losing these signals from the ear would cause the auditory brain regions to be less active. But in people with tinnitus, exactly the opposite occurs. The brain areas mediating hearing become hyperactive, their neurons firing off signals willy-nilly. That’s why tinnitus sufferers perceive sounds that aren’t really there.

Scientists have debated where this brain hyperactivity comes from: is it generated intrinsically or driven by abnormal signals from the ear? Since the ear cells aren’t overly active following noise damage, some researchers believe that it can’t be their fault that the brain is hyperactive.2 Sounds reasonable, right? On the other hand, some recent animal studies suggest that the ear is in fact part of the problem, because silencing signals from the ear can reduce hyperactivity in the brain—as long as the silencing is performed soon after noise damage.3,4

These results suggest that there may be two phases of tinnitus: an early phase when signals from the ear drive hyperactivity in the brain, and a later phase when brain cells have become so excitable that they remain hyperactive regardless of ear input. If this model is true, then there may be a critical window early after tinnitus onset during which reducing signals from the ear can ameliorate the condition.

Seeking treatment

A handful of medical papers suggest that furosemide, a drug used to treat high blood pressure and edema (swelling due to fluid retention), might reduce tinnitus in some people.5,6 Furosemide has long been known to decrease the spontaneous signals sent from the inner ear to the brain, likely by acting on molecular transporters that affect how excitable the cells are.7 By reducing signals from the ear, can furosemide also diminish hyperactivity in auditory brain areas and thereby alleviate tinnitus itself?

This is the question that a team at the University of Western Australia, led by Dr. Wilhelmina Mulders and Dr. Donald Robertson, wanted to address in an animal model. Obviously, the best way to determine whether furosemide can really treat tinnitus is to conduct carefully controlled studies on human patients. But before commencing human studies it’s essential to first verify that a drug is effective in animal models, as well as trying to understand how it actually works in the body.

In the mind of a guinea pig

Guinea pig

guinea pig glamour shot (credit: National Human Genome Research Institute

In their study (published this year in the journal PLoS One),8 Dr. Mulders’ team used guinea pigs as a model for studying tinnitus. Guinea pigs have long been used in auditory studies because some aspects of their hearing are quite similar to that of humans.

You might be wondering, how on earth can we tell if a guinea pig’s ears are ringing? Indeed, diagnosing an animal with tinnitus requires carefully designed experiments. The idea is that if an animal is experiencing a continual ringing in its ears and you play a background sound with a similar pitch to that ringing, then the animal won’t notice when there’s a silent gap in your sound.

Now, astute readers will recognize that this trick only slightly simplifies the problem of getting inside the guinea pig’s mind: we still need to determine whether or not the animal has “noticed” the break in the sound. It turns out that you can test what a guinea pig is hearing based on the fact that animals (including people) are startled by a loud noise, but they’re less startled if you give them a different cue just beforehand. It’s a way of telling their nervous system to prepare for the loud noise. The predictor cue can be a sound, or, conversely, a gap of silence amidst a background sound.

So finally, here’s something we can actually measure: the startle response manifests as an increase in movement, like when you jump in response to a loud noise. By comparing an animal’s startle response with and without different predictor cues, you can infer what the animal is hearing (see table above). For example, an animal with tinnitus won’t be able to detect a silent gap, so using the silent gap as the predictor cue won’t diminish its startle response as it does in normal animals.

how to assess tinnitus in guinea pigs

Table showing how the startle test can determine whether an animal has a general hearing defect and/or tinnitus.

Promising results

Dr. Mulders’ team first induced hearing damage in the guinea pigs by playing an extremely loud sound into one of their ears with a tiny speaker. (The animals were anesthetized during this procedure.) The animals’ hearing was then tested over the next several weeks. 40% of the guinea pigs couldn’t detect silent gaps within a sound, though they could still hear sounds in general, suggesting that they had tinnitus.

The researchers then injected some of these guinea pigs with furosemide and retested their hearing. Amazingly, this treatment basically eliminated their signs of tinnitus. Animals that did not receive the drug showed no improvement.

Mulders data

Data from Mulders et al. showing that furosemide ameliorates tinnitus in guinea pigs. “GPIAS” represents how well animals can detect a silent gap (lower GPIAS = more tinnitus). “AT” stands for acoustic trauma, i.e. noise damage. Black bars represent animals that eventually received furosemide; white bars represent control animals that received saline. Noise damage initially caused all animals to get worse at detecting silent gaps (middle bars). After drug or saline treatment (right bars), furosemide-treated animals recovered their ability to detect silent gaps, while control animals did not improve.

How does furosemide produce this striking effect? Dr. Mulders’ team demonstrated that not only does furosemide reduce activity in the ear, as previously described, it also reduces activity in an auditory brain region called the inferior colliculus. These results suggest that signals from the ear indeed seem to drive the brain hyperactivity that causes tinnitus, at least during certain stages of the disorder. By reducing activity in the ear, furosemide disrupts this process and ameliorates tinnitus.

Importantly, in this study furosemide had little effect on the hearing sensitivity of the ear (i.e., how well it responds to sounds), which is critical for its potential therapeutic use. This may seem surprising, given that I’ve told you that furosemide decreases the activity of neurons in the ear. The key is that furosemide specifically reduces spontaneous neural firing—meaning what the neurons are doing when there aren’t any sounds present. Apparently you can mess with their spontaneous activity and still have them respond to sounds perfectly well.

Overall, this study by Mulders et al. represents both a scientific and medical advance in the field. Not only does it shed light on the brain mechanisms underlying tinnitus, it also provides evidence for a possible therapeutic intervention. Of course, these results may not translate directly to humans. The authors themselves point out several reasons why human patients might not respond to furosemide as well as their guinea pigs did. For example, the drug’s effect was only tested once in each guinea pig, so it’s possible that its beneficial effects would eventually wear off. The sample sizes in this study were also very small, with only 3 to 4 animals per group.

For these reasons, further research will undoubtedly be needed to determine whether furosemide represents an effective treatment for human tinnitus. Nonetheless, this study offers hope that in the near future, tinnitus sufferers may finally be able to get some peace and quiet.

 

Notes:

1. Langguth B, Kreuzer PM, Kleinjung T, De Ridder D. Tinnitus: causes and clinical management. Lancet Neurol 12:920-930 (2013).

2. Eggermont JJ, Roberts LE. The neuroscience of tinnitus. Trends Neurosci 27:676-682 (2004).

This review article cites several studies showing that tinnitus can exist even when the level of activity in the ear is normal.

3. Mulders WH, Robertson D. Hyperactivity in the auditory midbrain after acoustic trauma: dependence on cochlear activity. Neuroscience 164:733-746 (2009).

4. Mulders WH, Robertson D. Progressive centralization of midbrain hyperactivity after acoustic trauma. Neuroscience 192:753-760 (2011).

5. Risey JA, Guth PS, Amedee RG. Furosemide distinguishes central and peripheral tinnitus. Int Tinnitus J 1:99-103 (1995).

6. Cesarani A, Capobianco S, Soi D, Giuliano DA, Alpini D. Intratympanic dexamethasone treatment for control of subjective idiopathic tinnitus: our clinical experience. Int Tinnitus J 8:111-114 (2002).

7. Sewell WF. The relation between the endocochlear potential and spontaneous activity in auditory nerve fibres of the cat. J Physiol 347:685-696 (1984).

8. Mulders WH, Barry KM, Robertson D. Effects of furosemide on cochlear neural activity, central hyperactivity and behavioural tinnitus after cochlear trauma in guinea pig. PLoS One 9:e97948 (2014).


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