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Could reducing brain inflammation be a way to treat tinnitus?

Scientists in the US have identified a link between inflammation in sound processing regions of the brain and tinnitus in mice. They have discovered that a molecule called TNF-alpha is key to this link, and that blocking its activity reduced tinnitus in the mice. This research could be the first step towards developing an effective treatment for tinnitus. Tracey from our research team tells us more.

Tinnitus is a sound, usually ringing, hissing or roaring, heard in the ears or the head that has no external source. It affects around 10% of the population to some degree, and for some people, it has a significant impact on their daily lives. It’s thought to be caused by damage to the inner ear, often following exposure to loud noise. It’s also strongly linked to hearing loss – most people with tinnitus will also have some degree of hearing loss.

Hearing loss is known to cause inflammation in the inner ear and parts of the hearing brain (those parts that sound signals travel through first on their way from the ear to the brain). So researchers at the University of Arizona in the US studied whether this inflammation is more widespread throughout the hearing brain, and if so, if it could be linked to tinnitus.

What is inflammation?

Inflammation is part of the body’s immune response to infection or damage – when a part of the body is inflamed, it may feel hot, turn red, swell up and/or feel painful. When someone has an infection, or is otherwise injured, cells of the immune system travel to the damage or infection to combat it. To do this, they produce proteins called ‘cytokines’ – some cytokines promote inflammation as part of this fight, and are called pro-inflammatory cytokines.

Inflammation is a normal part of our body’s response to damage or infection, and in most situations, it’s a good thing, helping our body to repair itself. But it can go wrong, particularly if it becomes over-active or chronic, or when it happens because the immune system recognizes a normal part of the body as foreign and attacks it, which happens in autoimmune diseases like rheumatoid arthritis.

Inflammation and hearing loss

Inflammation caused by hearing loss is seen in two main ways; first, as an increase in activation of cells called microglia, special immune system cells found in the brain and spinal cord – they can remove invaders (like bacteria) and help co-ordinate the response to more persistent infections or damage. They also produce a pro-inflammatory cytokine called TNF-alpha, the other sign of inflammation caused by hearing loss.

Microglia and TNF-alpha aren’t just involved in inflammation, however. They’re both important for the normal working of the brain and spinal cord, with roles in nerve cell development and life cycle, as well as how nerves work. But they become chronically activated in hearing loss, so could they be involved in other hearing problems, like tinnitus?

That’s what the researchers in Arizona wanted to know. To find out, they exposed mice to loud noise to damage the inner ear, and then looked at TNF-alpha levels in a part of the brain called the auditory cortex, which is responsible for perceiving sound. Noise exposure increased the levels of TNF-alpha, and the microglia in this part of the brain were also more activated. This suggests that loud noise causes inflammation, even in parts of the hearing brain furthest from the ear.

Next, they went on to look at tinnitus in the mice, and how TNF-alpha might be involved.

How do we know if a mouse has tinnitus?

Tinnitus is a subjective condition – what that means is that we have no way (currently) of measuring it that doesn’t involve asking the person with tinnitus to describe it or rate it themselves. And we obviously can’t ask a mouse if it has tinnitus, or what it sounds like, or if it could rate it on a scale of 1 to 10! So researchers have developed ways to assess if noise-exposed mice have tinnitus, usually based around ‘gap detection’ – testing if the mice can detect a short gap in a constant, low-level background noise that happens just before a loud noise.

If the mouse can hear it, then over time, it learns that the gap means there’s about to be a loud noise, so they don’t jump as much when it happens. But if the mouse has tinnitus, that is, if it’s constantly hearing a ringing in its ears, then it won’t hear the gap warning it about the noise, so they jump just as much the tenth time it happens as they did the first time. Researchers can measure the size of the jump, or the ‘startle response’, and in that way, check if a mouse has tinnitus.

It’s controversial, and some researchers working in the field don’t believe it’s a measurement of tinnitus at all, while others think it’s an appropriate system to use. Other ways have been developed to assess tinnitus in animals, usually involving training the animal to do something in response to a sound stimulus. Again, the idea is that tinnitus will mask the sound so the animal doesn’t hear it, which will change their behavior – these tests take longer and can be more difficult to use, but they may be better assessments of tinnitus.

In this study, the researchers used both gap detection and a second method to assess tinnitus, which gives us more confidence that the effects they saw were real.

Testing the link between TNF-alpha and tinnitus in mice

The researchers looked at the differences between normal mice and mice that lack the gene for TNF-alpha after they were exposed to noise. They found that mice without TNF-alpha didn’t show the same signs of activated microglia, or the same behavioural signs of tinnitus as the normal mice. The lack of TNF-alpha seemed to protect them from developing tinnitus.

Conversely, the researchers also showed that increasing levels of TNF-alpha in the auditory cortex induced tinnitus in both groups of mice in the absence of any noise exposure.

This points to TNF-alpha having a role in tinnitus caused by exposure to loud noise.

Can blocking TNF-alpha also block tinnitus?

There are drugs that can block the activity of TNF-alpha – they’re used to treat conditions like rheumatoid arthritis.

The researchers chose such a drug, called dTT, which reduces inflammation in the brain, and looked at what happened when mice were exposed to loud noise, but also treated with dTT, to block the TNF-alpha. In these mice, levels of TNF-alpha didn’t increase, and there were no signs of tinnitus. They showed similar results using their second tinnitus method too, increasing our confidence that blocking TNF-alpha really can block tinnitus from developing – at least in mice!

What does this mean for treatments?

These findings are potentially exciting, as they could point to a new way of treating tinnitus, and there are already drugs available that can block TNF-alpha.

However, this research was carried out in mice, and as yet, we don’t have any evidence that we’ll find the same in people. Until further research is carried out to confirm these findings in people, we can’t know if these treatments could be effective against tinnitus.

And even if this is the case, these treatments still need to be tested specifically as treatments for tinnitus before they can be used clinically – they might not be effective. In addition, TNF-alpha is part of our body’s defence against infection and damage – so blocking it could have unintended side effects which also need to be tested for.

So, although this is an encouraging first step, there’s still plenty of research to be done before we can get to a treatment.

Further information

This research was published earlier this month in the journal PLoS Biology, and you can read the abstract on the journal website.

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