Inner Ear Hair Cell Regeneration — Maybe We Can Know More

What you can do is just tell them that you can't understand well in noisy environments and get a treatment! They won't be able to verify it on the audiogram anyway!

When do you think trials for hidden hearing loss will start? I hope it doesn't take too long.

I read the other day that olfactory receptor cells can regenerate naturally, including the olfactory nerve cells.

Can you post a link to the video?

 

My audiogram looks pretty much normal. I only had a small dip at 6 kHz, about 30 dB. Which seemed to have recovered to 15 dB 2 months later. Not sure what to make of it. But I suspect I have some sensorineural damage in this region of the cochlea.

 

Eligible for what exactly? Hair cell restoration?... There are many people with perfectly normal looking audiograms who still have hearing loss. So called hidden hearing loss.

 

Where do you get that kind of audiogram? All my audiograms go up to 8 kHz only. A 30 dB dip that I had indicates mild hearing loss. Yours is also a mild hearing loss, at 40 dB. It's just that you are invisible, you are not considered someone with hearing loss unless the loss is within the 8 kHz. Some audiologist decided probably that it should be like that. Ultimately, everyone has some level of hearing loss, regardless of cause.

 

Who? Frequency? Someone will, at some point. Once hidden hearing loss is recognized as a real hearing disorder, and once we get better diagnostic instruments. That may take time. But it will happen eventually.

 

I agree! But how? The only thing that comes closest to answering this type of question are the µOCT probes they are developing at MEE/HMS and SU/TAMU.

Could we use electrocochleography and otoacoustic emissions? I am not so sure, but these seem like the most advance tests we have currently available that can help objectively answer this type of question.

Oh that narrows it down! No worries, you don't have to post a link. I understand it was a TV program.

As I said, the olfactory receptor cells, as well as the olfactory nerve has endogenous regenerative capability.

https://en.wikipedia.org/wiki/Olfactory_epithelium

https://en.wikipedia.org/wiki/Olfactory_nerve

Australian professor Alan Mackay studied the sense of smell for decades. His studies helped a team of British and Polish doctors make a Polish firefighter walk again after an injury. They used olfactory stem cells if I remember correctly.

Bravo for Alan Mackay, and bravo for olfactory nerve and olfactory receptor cells. Unfortunately, the cochlear nerve and the cochlear receptor cells don't posses this capability. Which is why I believe most of us are here today. If these had endogenous regenerative capability we would most likely not be here today because we would not have a problem.

Nerve damage in the CNS is most difficult to repair. There are a couple of reasons for this. But one of the reasons is that there are no Schwann cells in the CNS. The most promising therapy for repair of the CNS is cell transplants. The cochlear nerve branches off from the vestibulocochlear which is considered to be part of the PNS, and it has Schwann cells. But it seems to me that it has lost its regenerative capability. The hardest part is the demyelinated processes that innervate the hair cells. We need to be able to repair these if they are damaged, which seems to me much easier than repairing nerve damage in the CNS. So I would say that the outlook for cochlear nerve repair is very good.

 

First of all, if you already have T, then it's likely that you already have either synaptic or sensory loss, or both. Which one contributes more to T? No one knows for sure. They may both contribute equally, depending on the extent of the damage in each case of course. But Liberman seems to think that synaptic loss plays a bigger role in T than sensory loss.

If you have no sensory, or neural damage, good for you! Protect your ears and you may never get T. If you have some T that is caused by either sensory or neural damage, and you don't want it to get worse, then likewise, you need to protect your ears. What to protect more, nerves or hair cells? Protect them both! Because this seems to be what you're asking.

Just don't overprotect, your ears need stimulation. But avoid unnecessarily loud environments, and use protection when working with or close to loud machines, etc. Put your hands over your ears when you are close to an emergency vehicle siren, fire alarms, etc. But don't go carrying protection all the time, that may make things worse.

These theories are all based on the assumption that T is of cochlear origin. Then you have theories that point to other parts of the auditory system, higher up the system, like dorsal cochlear nucleus. No one knows for sure. But there is a strong body of evidence building up.

The synapse is the connection itself. And yes, this may be true. I have read about one theory that suggests that T is caused by cross-wiring of sprouting, unmyelinated nerve fibers. If true, this may be made even worse if these nerve fibers have lost their synaptic connection at the hair cells.

Not true! Have you had a look at the work of Susan Shore? Have you seen the latest report from University of Leicester? Or the MDMA study in New Zealand? Or the heredity study in Sweden?

Let's wait and see how these regenerative therapies play out.

This may not be possible without our help. So we may need one treatment for regrowing hair cells, and one for regrowing and reattaching neurons to them.

I know there was one recent study by Liberman that showed regrowth of nerve fibers, mediated by neurotrophin 3.

http://www.nature.com/articles/srep24907

 

Thanks!

I still don't know what episode it was, but they can be found here:
http://www.bbc.co.uk/programmes/b08ghp29/episodes/player

You were right about viewing restrictions. But at least UK viewers can watch it, if anyone is interested.

 

No, but that's even better. That kind of technology is excellent for CNS diseases, such as Alzheimer's.

We would be happy with something less advanced, and less expensive, but something more objective than the audiogram.

Something like this:
http://www.nature.com/articles/srep33288

Here is the related thread I started earlier on inner ear imaging:
https://www.tinnitustalk.com/threads/where-do-we-stand-on-inner-ear-imaging-technology.19580/

 

Besides true NT-3 and BDNF, several different BDNF mimetics have been identified, some of which have been newly synthesized as part of the NanoCI project. They are proteins that mimic the BDNF, with the advantage that they have longer half-life and are easier to produce and manage. There were two mimetics that were more effective than the others. One is called LMMA-2 or L2 for short, the other one is Trihydroxyflavone or THF for short.

Normal innervation

This is an illustration of a normal inner ear.


From top to bottom, you see the three ducts of the cochlea shaded in brown: scala vestibuli, scala media, scala tympani. The nerve fiber and the hair cell is shaded in green. The synapse is shaded in yellow.

CI innervation

This is an illustration of an inner ear that has received a cochlear implant.



This is not just any CI, but the very latest in CI technology. Here you see the kind of biochemical and bioengineering tricks that the NanoCI project was dealing with.

Green still represents the nerve fiber, and yellow represents the synapse. But instead of a hair cell on the other side, you see a cross section of the electrode, shaded in pink. Each synapse is an interface between a nerve fiber and an electrode contact. The synapses shaded in yellow in this illustration do not co-exist on the same plane, it just looks that way from this point of view. Remember it's a cross section.

I don't want to explain every detail. I should not have to. All the details can be found on this website:
http://www.nanoci.org/index.php

It's fascinating to see what they have accomplished. I know people on this forum are not looking for a cochlear implant. But nevertheless! The results of projects like this one are still relevant to us all. The most striking feature on the illustration above is how they were able to attract the nerve fiber to the electrode. This was done by releasing NT-3 or BDNF mimetics from a reservoir in the electrode. Really cool stuff!

The illustration only shows one nerve fiber, because it's an illustration. In real life, there would have been multiple nerve fibers connecting to multiple electrode contacts. What's also new about this CI electrode is that it has three times more contacts and channels than what we see in current CI designs.

Attraction of nerve fibers by electrical stimulation is something that professor Helge Rask Andersen of Uppsala university has been contemplating ever since he demonstrated otic nerve fiber regeneration over a decade ago. I won't say it's signed by him, but this work is clearly influenced by him.

I don't know about drugs for regrowing otic nerve fibers exclusively. But the NanoCI project may be an inroad for that. They can synthesize LMMA-2. That's a beginning of a drug. Besides, NanoCI was never about CI exclusively.

Quote from the final report:

"A total of 4 patents to protect intellectual property related to NANOCI have been filed or are in preparation at the end of the project. In addition, over a dozen individual exploitation tracks have been identified, which will be pursued beyond the NANOCI project. These exploitation tracks include further developments of neurotrophin biomimetic molecules, nanomatrix gels, conductive and antibiotic nanoparticles, optic sensors, mathematical neuron models, in vitro and in vivo bioassays (as shown in Figures 3, 4 and 5), controlled drug-release and medical imaging technologies (as shown in Figure 6), among others."

 

Correct! Not as far as I know.

I don't know how far they have come. But the Stanford team has made a relatively recent update on their blog.

Professor Stefan Heller quote:

"John Oghalai’s research group has designed and created an instrument allowing the visualization of the inside of the mouse and human cochlea. The resolution of this novel imaging method, called optical coherence tomography (OCT), is much better than existing methods such as CT scans or MRI. It does not require radiation and it does not require huge magnets; in fact it can be done during or just before surgery. Five years ago, Dr. Oghalai’s OCT scanner was about the size of a pickup truck. Version 2 was the size of a large suitcase. The current version of the instrument is the size of a shoebox! We envision that in the next five years, the technology will be tested on human patients when planning inner ear surgeries such as the placement of cochlear implants."

Source: https://hearinglosscure.stanford.edu/2017/02/sichl-and-the-past-present-and-future/

 

This may be old news, but this is one of the first time-lapse videos showing otic nerve axonal sprouting, mediated by BDNF, NT3 and GDNF. Image capture interval is three minutes.

Hörselnerv som utvecklar axoner

You can see how the cells seek out each other and hook onto one another and form a ganglion. It's a process called axonal pathfinding, in particular, the mechanism in action is called fasciculation.

This video is recorded in 2005 at Uppsala university, but I think the original work was done in 2004 at the lab of professor Helge Rask Andersen. It was professor Helge and his associates that found immature stem cells in the inner ear of adults, a sensational piece of news in the research world at the time.

A more recent press release can be found here:
http://www.mynewsdesk.com/se/uu/pressreleases/cell-transplants-may-cure-deafness-288512

Here is a more recent video from Uppsala showing human neural progenitor cells differentiating on a Multi Electrode-Array (MEA).

Neurala stamceller som utvecklas till...

The non-transparent squares are electrodes through which cells can be electrically stimulated as well as monitored for spontaneous electrical activity. As the cells mature several axons sprout and form bundles between neighboring cell clusters thus creating a neural network.

 

Yeah, I saw that one too. What strikes me the most is that you need to have a synaptic loss of 80% before it's noticeable on a standard audiogram.

 

Source: https://decibeltx.com/our-platform/

This seems to suggest that Decibel is not only interested in regenerating hair cells, but identifying the underlying cause of hearing problems, and targeting these. I think it's very likely that Decibel might be the first company to target synapse regeneration.

Does anyone have any news on their progress? They have been quite for some time now. Meanwhile, Frequency is in the spotlight all the time and on everyone's mind. I would like to see them announce a clinical trial, even if it's far off into the future. We would have something to relate to. Frequency has been repeatedly saying they will do a trial in 18 months and it's always the same number. They even post articles that mention them as news. They definitely have a better PR department.

 

It might be! I would say that tinnitus in Meniere's disease is most likely caused by hydrops. It's the endolymph chemical changes affecting the synapses during an attack. Having these attacks long term may damage the synapses permanently. That's why your coworker should avoid eating too much salt. There is in fact a special diet recommendation for people with Meniere's disease.