Inner Ear Hair Cell Regeneration — Maybe We Can Know More

[Samir]

Not perception. I understand the ear is like a pick-up device. The brain interprets.
I was wondering if the conscious brain is able to "control" the outer hair cells to a certain extend.
I know that for the eye we are not consciously able to control our iris. That is al automated

Thanks for clarifying! I now understand what you mean.

I wonder if we concentrate on certain regions in sound (as an example higher frequencies in music) we can make this part of the cochlea more sensitive "using" the outer hair cells.
Or is it only the brain that is responsible for this "tuning in".

Good question! Without knowing much about it really, my guess would be that it's all the brain controlling any kind of tuning. But the ear and the brain do work together on the lowest, cellular level.

I agree that both brain and inner ear research is needed for this. I don't have a clue which field is less complex.
They both sound very, very complex to me.

Agreed!

In an ideal world it would be logical to fix the cause of the problem. For me (and many people) that would be damaged inner ears.

Agreed!

Although I have read that there is a possibility with NIHL the brain is also effected.

The brain is definitely affected. If not by signal deprivation from cochlear lesions, then by cellular damage in the early stages of the auditory pathway. Or the reorganization that takes place at higher levels.

 

[Aaron123]

Not directly hair cell regeneration related, but relevant to the general discussion:

Interesting new paper out of Liberman's lab: http://www.sciencedirect.com.libproxy.uncg.edu/science/article/pii/S0378595517301168

They look at synaptopathy in a primate (rhesus monkeys). For given noise levels primates suffer less hair cell damage than other mammals (e.g., mice). However, synapse damage appears to be similar between primates (this one anyway) and other mammals.

This is also the first paper I recall seeing evidence of synaptopathy associated with PTS.

 

[Reinier]

This is also the first paper I recall seeing evidence of synaptopathy associated with PTS.

It suggested that PTS is able to induce synaptopathy? Not just noise?

I am not able to read the paper.

 

[Reinier]

But the ear and the brain do work together on the lowest, cellular level.

Yes I understand. I realise in ancient times people needed to be able to concentrate hearing when life threatening situations arose. (Like when potential predators are part of life).
But that part is like the iris in our eyes not on a conscious level. I also understand that this concentration of hearing is partly done by the outer hair cells.
Wouldn't it be amazing if we can do this consciously

 

[Flamingo1]

For given noise levels primates suffer less hair cell damage than other mammals (e.g., mice). However, synapse damage appears to be similar between primates (this one anyway) and other mammals.

Can the body repair/regenerate synapses? Or is this damage also permanent?

 

[Aaron123]

Can the body repair/regenerate synapses? Or is this damage also permanent?

It is permanent.

 

[Flamingo1]

It is permanent.

Crap. From reading the research threads, I understand there are some start-ups that are looking to reverse synaptic damage but to me this seems like an impossible task. From my limited knowledge, hair cell regeneration sounds more achievable (but I could hopefully be wrong!)

 

[lapidus]

Crap. From reading the research threads, I understand there are some start-ups that are looking to reverse synaptic damage but to me this seems like an impossible task. From my limited knowledge, hair cell regeneration sounds more achievable (but I could hopefully be wrong!)

I think I read somewhere it was the other way around. That restoring nerve synapses would be easier than restoring hair cells. Can't remember where I read that though. Maybe it was Liberman who said it, please correct me if I'm wrong.

 

[addot]

I think I read somewhere it was the other way around. That restoring nerve synapses would be easier than restoring hair cells. Can't remember where I read that though. Maybe it was Liberman who said it, please correct me if I'm wrong.

http://www.newyorker.com/magazine/2017/04/03/high-tech-hope-for-the-hard-of-hearing

"What we discovered is that it's actually the connections between the sensory cells and the nerve fibres that go first," Liberman told me. "They are much more vulnerable than the sensory cells."
(...)
Nonetheless, among researchers, the discovery has been a cause for optimism, because reconnecting nerve synapses is almost certain to be easier than regenerating functioning hair cells inside human ears. "This is the simplest sensory circuit that you could possibly have," Liberman said. "It's one sensory cell type and one neuronal cell type, and it's possible to do local delivery through the eardrum." He and others have successfully restored some damaged connections in lab animals, and he believes that far greater advances are to come.

 

[Flamingo1]

Thanks @addot!

 

[jer]

Everyone thought at one point that regenerating hair cells would be impossible, and look where they are now! So before you know it, they will have found a way to repair the synapses too. Remember, about 10 years ago nobody heard of an iPhone, and the blackberry with keyboard was the best thing out there. Look at where we are today! Never bet against science and innovation. That is one thing I've learned over the years.

 

[Frédéric]

I don't think this article from Liberman has already been posted in this forum since it has been published today :

Noise-induced and age-related hearing loss: new perspectives and potential therapies [version 1; referees: 4 approved]

M Charles Liberman

Abstract
The classic view of sensorineural hearing loss has been that the primary damage targets are hair cells and that auditory nerve loss is typically secondary to hair cell degeneration. Recent work has challenged that view. In noise-induced hearing loss, exposures causing only reversible threshold shifts (and no hair cell loss) nevertheless cause permanent loss of >50% of the synaptic connections between hair cells and the auditory nerve. Similarly, in age-related hearing loss, degeneration of cochlear synapses precedes both hair cell loss and threshold elevation. This primary neural degeneration has remained a "hidden hearing loss" for two reasons: 1) the neuronal cell bodies survive for years despite loss of synaptic connection with hair cells, and 2) the degeneration is selective for auditory nerve fibers with high thresholds. Although not required for threshold detection when quiet, these high-threshold fibers are critical for hearing in noisy environments. Research suggests that primary neural degeneration is an important contributor to the perceptual handicap in sensorineural hearing loss, and it may be key to the generation of tinnitus and other associated perceptual anomalies. In cases where the hair cells survive, neurotrophin therapies can elicit neurite outgrowth from surviving auditory neurons and re-establishment of their peripheral synapses; thus, treatments may be on the horizon.

Full text : https://f1000research.com/articles/6-927/v1

 

[jacob21]

@Frédéric Interesting

However, neurotrophins therapy is still far from my understanding
https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/2047-9158-1-14

 

[Flamingo1]

@Frédéric Interesting

However, neurotrophins therapy is still far from my understanding
https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/2047-9158-1-14

From the article:

Although there are strong rationales suggesting that increasing supply of neurotrophins to degenerating neurons may be a potent way to restore neuronal function in neurodegenerative conditions, delivering neurotrophins into the brain has proven to be a non-trivial matter.

I believe the goal is to treat synapses at the ear hair cell, not in the brain.

 

[Melike]

The brain is definitely affected. If not by signal deprivation from cochlear lesions, then by cellular damage in the early stages of the auditory pathway. Or the reorganization that takes place at higher levels.

Do you think that those without any measurable hearing loss have that reorganization in their auditory cortex just because of the recent phenomenon that the loss of synaptic connections without hair cell loss? Or do you believe neuronal reorganization may have nothing to do with any cochlear damage?

 

[Samir]

Do you think that those without any measurable hearing loss have that reorganization in their auditory cortex just because of the recent phenomenon that the loss of synaptic connections without hair cell loss?

I presume you are referring to the recent discovery rather than phenomenon, better known as hidden hearing loss.

No, not just because of that. Hidden or not, hearing loss may still trigger the reorganization of the auditory cortex. But we still don't know if it's that reorganization that leads to tinnitus, do we? It's still just a working hypothesis.

Or do you believe neuronal reorganization may have nothing to do with any cochlear damage?

More importantly, is it the cortical reorganization that leads to tinnitus?

Note that we are primarily talking about noise induced tinnitus. It is often said that tinnitus can be triggered by a number of things, not just hearing loss. I think it may be worsened by other factors, such as stress, depression or even sleep deprivation. But a majority of those who have tinnitus have had some kind of noise trauma. The damage caused by a noise trauma will normally be visible on an audiogram, if the damage is severe enough. However, there are people who can pass a standard audiogram with normal results but still have tinnitus. I personally fall into this category. It was only indicated recently that people who have a normal audiogram but complain about tinnitus, hyperacusis or not hearing well in noise environment, may in fact have hidden hearing loss.

There are a couple of questions to this.

1. Does noise trauma lead to cochlear damage?
2. Does cochlear damage lead to cortical reorganization?
3. Does cortical reorganization lead to tinnitus?

The first one has been answered. The answer is yes! What we are trying to figure out now is how much trauma leads to how much damage, and in what regions of the cochlea. What it does to the brain and other structures we have hardly explored.

It has dawned on me, unfortunately too late now, that those delicate inner ear structures are very sensitive and fragile. Most of us seem to think that sound is magic, especially when you think about music. You play a piece of recorded music and you sit down 20 feet away from the loudspeaker to enjoy it. You can hear the music, but you are untethered from the loudspeaker. There is nothing in-between the listener and the speaker. Like magic! But there are mechanical waves hitting your eardrum every microsecond! You cannot sense the energy coming out of that loudspeaker unless you are playing it very loudly. If you play it so hard that the furniture and windows shake, then you can be sure you are damaging your ears.

In short:
Yes, I do think that ribbon synapses are more prone to damage than hair cells.
Yes, I do think that cochlear damage can lead to cortical reorganization.
Yes, I do believe in hidden hearing loss.
Yes, I do think that other factors than hearing loss may play a role in cortical reorganization.
No, I don't know if cochlear damage leads to cortical reorganization.
No, I don't know if cortical reorganization is what causes tinnitus.

 

[VRZ78]

I don't think this article from Liberman has already been posted in this forum since it has been published today :

Noise-induced and age-related hearing loss: new perspectives and potential therapies [version 1; referees: 4 approved]

M Charles Liberman

Abstract
The classic view of sensorineural hearing loss has been that the primary damage targets are hair cells and that auditory nerve loss is typically secondary to hair cell degeneration. Recent work has challenged that view. In noise-induced hearing loss, exposures causing only reversible threshold shifts (and no hair cell loss) nevertheless cause permanent loss of >50% of the synaptic connections between hair cells and the auditory nerve. Similarly, in age-related hearing loss, degeneration of cochlear synapses precedes both hair cell loss and threshold elevation. This primary neural degeneration has remained a "hidden hearing loss" for two reasons: 1) the neuronal cell bodies survive for years despite loss of synaptic connection with hair cells, and 2) the degeneration is selective for auditory nerve fibers with high thresholds. Although not required for threshold detection when quiet, these high-threshold fibers are critical for hearing in noisy environments. Research suggests that primary neural degeneration is an important contributor to the perceptual handicap in sensorineural hearing loss, and it may be key to the generation of tinnitus and other associated perceptual anomalies. In cases where the hair cells survive, neurotrophin therapies can elicit neurite outgrowth from surviving auditory neurons and re-establishment of their peripheral synapses; thus, treatments may be on the horizon.

Full text : https://f1000research.com/articles/6-927/v1

I dont really see what's new from the article he wrote last year....

Hopefully Décibel is working on it

 

[Melike]

But we still don't know if it's that reorganization that leads to tinnitus, do we? It's still just a working hypothesis.

well, you certainly have a better understanding for the recent literature than mine, I'm not sure if it is proven to be a 'reorganization' leading to tinnitus. But I can say that my fMRI scans show some 'disorganization' as they interpreted it. I've seen a few others' scans indicating the same thing even though their tinnitus have different causes.

Yes, I do think that ribbon synapses are more prone to damage than hair cells.

Yes, I do think that cochlear damage can lead to cortical reorganization.
Yes, I do believe in hidden hearing loss.
Yes, I do think that other factors than hearing loss may play a role in cortical reorganization.
No, I don't know if cochlear damage leads to cortical reorganization.
No, I don't know if cortical reorganization is what causes tinnitus.

Based on what I've read so far with limited understanding of medical terms, thats what I conclude at the moment. I %100 agree.

According to Josef P. Rauschecker, any kind of cortical reorganization should be consequence of a cochlear damage. But there is a study ;

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269775/

A significant difference in evoked response magnitude was found near the low-frequency tonotopic endpoint on the lateral extreme of left Heschl's gyrus.

That might also seem as 'disorganization' in fMRI scans, tho. But doesnt necessarily have to be a reorganization.

What do you think about his theory of compromised the ventromedial prefrontal cortex (VNPFC) and the anterior cingulate cortex for tuning out that noise?

 

[Samir]

I can say that my fMRI scans show some 'disorganization' as they interpreted it. I've seen a few others' scans indicating the same thing even though their tinnitus have different causes.

That is very interesting, and definitely something worth exploring more.

By reading my recent comments, it may seem like I am against neuroscience. I am not against neuroscience per se, and following other research and treatment routs, something other than restoring hair cells or ribbon synapses. But I would like to see more work in that area, specifically toward better understanding, and hopefully treating tinnitus successfully in the future.

Right now, I feel like hair cell restoration is the best route. At least we will be able to settle this once and for all. We will know for sure if restoration of these cells can attenuate or cure tinnitus. I know how difficult this is. But what do we have to lose? What better option does neuroscience and neurology have in store for us? I can only urge neurosciences to hurry up and come up with a viable treatment option.

A significant difference in evoked response magnitude was found near the low-frequency tonotopic endpoint on the lateral extreme of left Heschl's gyrus.

This is their own conclusion:

Our results suggest that macroscopic tonotopic reorganization in the auditory cortex is not required for the emergence of tinnitus, and is not typical for tinnitus that accompanies normal hearing to mild hearing loss.

I interpret this as meaning the following:
1. Cortical reorganization is present in the tinnitus patient.
2. The reorganziation does not have to be significant for tinnitus to emerge – meaning it can be minor too.
3. Reorganization is minor (microscopic) in normal hearing.
4. Reorganization is minor (microscopic) in mild hearing loss.
5. Reorganization is major (macroscopic) in hearing loss greater than mild.

(Note, by "normal hearing to mild hearing loss" they likely meant to say "normal hearing or mild hearing loss". Normal hearing is not a loss. In quotation marks, "normal" hearing. They cannot really objectively asses what is normal hearing, can they? Given the evidence of hidden hearing loss and all those bits.)

That is my own interpretation anyway.

That might also seem as 'disorganization' in fMRI scans, tho. But doesnt necessarily have to be a reorganization.

I am not sure I understand what you mean by "disorganization" vs. "reorganization".

It might just be that what they think they know they see on the scan is far from reality. They need to do more research, and with better tools. The subjective nature of tinnitus is one of the greatest challenges in this disease. I call it disease, because that's what it is. The professionals can call it a symptom all they want, I know different.

What do you think about his theory of compromised the ventromedial prefrontal cortex (VNPFC) and the anterior cingulate cortex for tuning out that noise?

That sounds like something professor Rauschecker would say. The "gate keeper" theory! I am not a professional neuroscientist, I don't really know what any of these are. But it could hold true?! Why not? Other neuroscientists perhaps need to investigate this further.

 

[Reinier]

I am not against neuroscience per se, and following other research and treatment routs

I have been reading a lot these last two years regarding tinnitus. I am starting to notice that a very large percentage of people that have bothersome tinnitus have been, or still are emotionally effected.
A lot of people seem to need both stress and NIHL for tinnitus to surface. Not NIHL being the trigger for tinnitus, but stress. A little difficult to explain what I mean for me in the English language.

I think that if brain and neurosciense researchers work with inner ear researchers, we can expect earliest results.
For me personally, my stress went through the roof after I realized the noise incident was irreversible.
This stress remained extremely high for a very long time. That makes me think that things have changed in my brain and that perhaps makes the tinnitus permanent.

 

[Melike]

Right now, I feel like hair cell restoration is the best route. At least we will be able to settle this once and for all. We will know for sure if restoration of these cells can attenuate or cure tinnitus.

I agree. But, if the tuning out mechanism in the limbic system is compromised, at least if that theory is actually true(which I believe), one can experience the exact same hell with another damage to his/her ear that easily again. Thats why I believe we need multidisciplinary treatments for successfully overcoming this condition.

I interpret this as meaning the following:
1. Cortical reorganization is present in the tinnitus patient.
2. The reorganziation does not have to be significant for tinnitus to emerge – meaning it can be minor too.
3. Reorganization is minor (microscopic) in normal hearing.
4. Reorganization is minor (microscopic) in mild hearing loss.
5. Reorganization is major (macroscopic) in hearing loss greater than mild.

The 'reorganization' takes place in totally unrelated frequencies for tinnitus patients with no&mild hearing loss. There is no evidence for any kind of overrepresentation for the frequencies that match the tinnitus pitch. As far as I know, with moderate & severe hearing loss, the 'reorganization' takes place in the edge frequencies of the hearing loss. Correct me if I'm wrong. So it has much more than just being 'macroscopic' or 'microscopic'.

I am not sure I understand what you mean by "disorganization" vs. "reorganization".

So, what I meant to say is the 'disorganization' as they interpreted in my fMRI scans might be that 'evoked response magnitude was found near the low-frequency tonotopic endpoint on the lateral extreme of left Heschl's gyrus' as mentioned in the study, rather than a 'reorganization' of the tonotopic map around the edge frequencies (I have no hearing loss). Sorry for not making myself clear. Thats why I was wondering what they mean with the 'disorganization' or how is that different from a 'reorganization', or is it even different?

I am not a professional neuroscientist, I don't really know what any of these are.

I know that you are not an expert. I just felt like you are pretty interested in the tinnitus related research, since you are also a 'team research' member, and wanted to hear your opinion. Thats all.

 

[Reinier]

Hough Ear seems to be concentrating on hidden hearing loss too.
I didn't realise that before.

http://houghear.org/hidden-hearing-loss/
quote: "In our research labs, we have both culture dish and live animal data showing we can regenerate these fine nerve connections and reconnect them to hair cells for hearing restoration."
It looks like they are so close.
How much is PR?

 

[Melike]

Hough Ear seems to be concentrating on hidden hearing loss too.
I didn't realise that before.

http://houghear.org/hidden-hearing-loss/
quote: "In our research labs, we have both culture dish and live animal data showing we can regenerate these fine nerve connections and reconnect them to hair cells for hearing restoration."
It looks like they are so close.
How much is PR?

Sounds very promising.

 

[jacob21]

Indeed they are very advanced HEI , They even know how to reach the cochlea
http://houghear.org/research-update-may-2017/

Really how we 'll see some trials on humans very soon !

 

[tomytl]

I wrote them many timesto ask some question considering their regeneration program but never got an answer.
I just hope they have really some advances close to clinical trial. They do their research very separated from all other research institures. I also didn't find many research papers about their regeneration program.
Probably someone knows more about their status.

 

[acufenero]

Here they say this about hair cell regeneration:

"Regenerating these delicate inner ear sensory cells in the cochlea has been thought impossible by some, but in our lab, which is one of only a handful of labs working on this problem, we believe we have found a way to do it.

[...]

The ability to participate in a project of this proportion that has the possibility of tremendous advancement within the hearing community is exciting; but this is not a fast project. We predict it will take eighteen months to two years and $930K to complete, but we do have partners that have committed $440K to date."

No idea when it was written, though.

 

[Autumnly]

According to this page, it was published: June 12, 2015 at 3:52 PM

 

[acufenero]

According to this page, it was published: June 12, 2015 at 3:52 PM

Cool. Then we may get some news later this year.

 

[tomytl]

Cool. Then we may get some news later this year.

Here they say this about hair cell regeneration:

"Regenerating these delicate inner ear sensory cells in the cochlea has been thought impossible by some, but in our lab, which is one of only a handful of labs working on this problem, we believe we have found a way to do it.

[...]

The ability to participate in a project of this proportion that has the possibility of tremendous advancement within the hearing community is exciting; but this is not a fast project. We predict it will take eighteen months to two years and $930K to complete, but we do have partners that have committed $440K to date."

No idea when it was written, though.

Usually I tend to be optimistic even I know that hair cell regeneration won't be an easy task.
But if they are so close, it wonders that they can't find fincancially support, 900k for such a discovery is almost nothing.

Otologic Pharmaceuticals licensed the technology already. From people, Otologic Pharma and Hough Ear are almost the same, both with Dr. Richard Kopke.
And Otologic is a part of the Acele Bio Company, which I don't know.

From what I read the past 10 years, they also work somewhat with the US Military, so there is probably some support.

For a company or institution with a solution in the lab, it's quite calm I think.

 

[Autumnly]

According to this page:

"Anticipating 85% Reduction in Government Grants
Grants from the National Institutes of Health, the Office of Navel Research, and Oklahoma Center for the Advancement of Science and Technology made seven years of pre-clinical studies possible, and until now, HEI has had little need for traditional fundraising or donor-based programs to support the research.

We are experiencing a major paradigm shift in our revenue and expense model and are planning on an 85% reduction in grants available for research from the federal government.

As a result, we are now seeking grants from private foundations, companies, and private donors to support critical research."

But I still agree that 900k shouldn't be too difficult to obtain if their research results honestly hold "the potential to restore hearing function or reverse tinnitus disorders".