Frequency Therapeutics — Hearing Loss Regeneration

[Daniel Lion]

The tensor tympani muscle doesn't get injured by sound itself. According to the paper it's the way it reacts to the sound that causes its own damage. It's like it goes into meltdown under the right conditions. I've quoted some bits from it,

It has been suggested that an acoustic shock (or trauma), potentially coupled to a particular emotional state, can cause a TTM hypercontraction (overuse) triggering a cascade of events leading to the symptom cluster

The resulting effect of this hypercontraction could be even more important if it occurs in the case of TTM vulnerability (muscle fatigue, chronic hypoxia), namely, during times where the TTM is under particular strain due to overload, stress and noisy and loud environments. Call centers, where many cases of acoustic shock have been reported, may combine all of these elements, including prolonged stress and strong focused auditory attention.

The hypercontraction linked to an acoustic shock or trauma could lead to a more or less severe musculoskeletal disorder of the TTM, from a simple stiffening of the muscle to a more severe and pathologic condition such as tear, chronic, and spasmodic contraction. The feeling of ear fullness may result from the deformation of the tympanum detected by the mechanoreceptors inside the tympanic membrane due to TTM contraction and the dysfunction of the TTM-tensor veli palatini muscle functional unit. I find this interesting because these 2 muscles (tensor tympani and tensor veli palatini) share a tendon and even work together and the pic of the tensor veli palatini shown below is a good example of a location where the facial pain occurs.

View attachment 40510

Injury of the TTM can be associated with many other adverse consequences. The main detrimental consequence of excessive and prolonged muscle contraction (muscle overload) is blood vessel compression. Importantly, this can result in a reduction in the local oxygen supply to the affected muscle. This phenomenon, in addition to a higher metabolic demand due to the prolonged contraction, can result in a reduction in the production of adenosine triphosphate (ATP) also called "ATP energy crisis". In this circumstance, the muscle switches to an anaerobic glycolysis state to provide the muscle with adequate ATP. Lactic acid is then produced and accumulates in the muscle which increases the local acidity. This decrease in pH (increase of extracellular protons) can activate acid-sensing ion channels of nociceptors, thereby exciting these neurons. A low pH can also downregulate acetylcholinesterase, increase the efficacy of acetylcholine, and maintain muscle contraction. Moreover, free Ca2+, needed for muscular contraction, has to return to the sarcoplasmic reticulum by the calcium pump for muscular relaxation. This process, however, is costly in ATP and cannot be properly done in case of severe energy depletion. The muscle thus stay contracted (until enough ATP is available), which could lead to further muscle injury.

---

Once the muscle enters this contraction/spasming cycle, the end result of how much damage there is depends on how quickly you remove yourself from the noise situation/how long it goes on for. And this is just the start of it. What it suggests happens next is that the middle ear damage starts generating proinflammatory molecules like ATP, and the nerves (trigeminal mainly) become sensitized, this sounds to me like the familiar inner ear type II afferent sensitization theory except it's happening in the middle ear.

TTTS also typically starts after an acoustic shock, it's another indicator that the middle ear has an ongoing problem now. The TTTS is apparently protecting the inner ear at a much reduced noise threshold and startle response. It is putting itself under undue strain, whilst still presumably not recovered, even for moderate noise so it makes sense that it doesn't take much more for this muscle to go into the above cycle even more easily with repeat setbacks. Not to say inner ear pain isn't also at play, but I can't ignore the amount of seemingly linked causes and symptoms in the middle ear and face anymore.

Thanks for your input @100Hz and @GoatSheep for initiating this discussion about the workings and malfunctioning of mechanisms in the middle ear. Sorry for the digression FX-322 fans, but we've got a lot of time on our hands, 8 months at least.

When I had an acoustic trauma I experienced muscle spasms, TTTS I think, that shot pain into my brain. It was like the spasms led to a stabbing sensation... ouchh. I have improved a lot, no more spasms and hyperacusis in check granted my noise thresholds are no where near normal and I do protect regularly from noise. So yeah, my bad ear is where the tinnitus rages and there's lots of clicking and muscle issues.

I noticed something, it wasn't a miracle, but it does help. I was searching through YouTube ages ago and found a stretch, where your lying down and raise and put your legs over your head. Is hard to do and your stomach ends up in your face. This stretch actually pulls muscles in the ear, you can literally feel it. It may help a few folks here to give some relief to stressed muscles and retrain them. I will find a link and post if anybody is interested.

Valium also helped relax muscles but I wound up crying half the day and was popping them like candy, it was unsustainable. Benzos do seem to help a lot of people here with ear muscle spasms.

I don't think FX-322 will help this kind of damage, but better hearing and less tinnitus would be a miracle. I can't wear hearing aids because of my hyperacusis and nerve damage even though my ski slope hearing loss makes me an excellent candidate. Thus my love affair with FX-322.

 

[tommyd87]

I agree with this - we're now starting to learn that the cochlea is far more vulnerable to damage than previously thought. According to hyperacusis.net acoustic shock is defined as "any sound that is perceived as threatening, usually a sudden/unexpected/loud sound heard near the ear. The sound is rarely loud enough or present for long enough to cause a noise induced hearing loss." But we now know that current methods to diagnose hearing loss are primitive - perhaps acoustic shock doesn't typically show up on a normal audiogram but it causes EHF loss or synapse loss, who knows?

I think noxacusis/acoustic shock in general can be seen as a bit of an extra special edge case disorder but I'm not sure, I have a gut feeling it's all linked to hearing loss fundamentally.

I've also seen this view expressed occasionally here that FX-322 won't help hyperacusis as Frequency Therapeutics haven't mentioned hyperacusis in any of their discussions about the drug. The way I see it, they're not purposefully omitting any mention of it because they believe it won't work for hyperacusis. I think it's more that hearing loss and tinnitus are far more common and well-known, both amongst the public and medical professionals. I always forget that outside of this forum and some research circles hyperacusis, and more specifically noxacusis is pretty unknown. I mean, I've seen figures that estimate its prevalence at 1 in 50,000 - Bryan Pollard said in his Tinnitus Talk Podcast interview that it's difficult to increase awareness when even doctors report that they may only see a handful of cases per year of disabling hyperacusis. Even experienced clinicians at major hospitals seem dumbfounded at the concept of noise-induced pain, in some cases. It took Cindy Redmond 6 months to get a diagnosis. The clinical world is far behind the research.

I also think, from a commercial standpoint, Frequency Therapeutics are really focused on meeting the needs of a significant 'unmet market' - hearing loss is extremely common and tinnitus too. I'm not necessarily alarmed by hyperacusis not factoring much into their discussions at the moment as it's not really a 'significant market' - but I think it will be interesting to see whether this will emerge as the trials progress. Not sure if that makes sense, just my take.

I think that hyperacusis has been a lot less understood condition compared with tinnitus. Therefore I think that it is not a matter of people totally ruling out that FX-322 will treat hyperacusis, but rather that a lot less is known about it. And so it cannot be said confidently that FX-322 will treat hyperacusis as effectively as it can treat tinnitus. Having said that, I still believe that there could be a positive outcome for hyperacusis with FX-322 (in addition to other hearing treatment medicines).

I think the key difference between tinnitus and hyperacusis is that the information from patients relating to tinnitus is far more detailed due to the higher number of people with tinnitus, as compared to hyperacusis. Therefore there can be more certainty around what the cause of tinnitus is (often being hearing loss) and also from a medicine perspective what would need to be treated to resolve the tinnitus symptom. The hyperacusis data is limited due to the relatively limited number of people who have it (which you have alluded to). However, I wouldn't be surprised if Frequency Therapeutics (or one or more of the other hearing related drug firms) started to investigate the influence the drug has on hyperacusis. I'd assume that this wouldn't be at the point of any of their initial trials, though I would suggest it would be done as a secondary measure.

 

[FGG]

So since I was rejected for the trial does that mean my time is coming soon?

I'm in the same boat. But I just asked my magic 8 ball and you will be ok at least.

 

[Billy_Shears]

I thought I'd share this interesting thought on the meaning of the numerical 322 supposedly from biblical times and being used today by Frequency Therapeutics on the hypothesis of FX-322 potentially being the Godsend for eradicating not only sensorineural hearing loss, yet an array of differing types of tinnitus.

"The 322 meaning promises you that once this transition period is over, you will feel relieved. You will emerge stronger and better. Angel numbers 322 want you to know that you are not alone during this period of transformation. You have the guidance of the divine realm, and you have the complete support of your guardian angels!"​

There is more hope for many individuals now than ever before.

 

[100Hz]

I think that hyperacusis has been a lot less understood condition compared with tinnitus.

Yes that's the trouble with it, so much speculation.

Humor me for one minute, I'll throw a wild hypothesis out there without going into too much detail.

There is zero significant cochlea damage after the acoustic shock, if any. The acoustic shock caused the symptoms cluster in the mid ear and it is now the damaged/highly sensitive/high emotional response/etc. affected mid ear that is causing all of the problems, the delayed pain, and the 'feeling' that noise is hurting the inner ear when in fact it isn't. In effect sound is reaching the unaffacted cochlea but is going through a highly dysfunctional, misfiring, erratic, nerve sensitizing middle ear minefield to get there leaving a trail of inflammation in its wake which is presenting the illusion that the cochlea is the problem.

One quick way this might be substantiated to some degree is say someone had a life of normal noise (both ears received the same over the years). One day they both get the same loud noise. One gets an acoustic shock, from that day forward that ear experiences noxacusis with heightened sensitivity, delayed pain, etc. and the other one doesn't. The difference between the 2 ears is the acoustic shock so why point the finger at the cochlea? The other cochlea has had the same noise only no acoustic shock and remains unaffected.

Again just another speculation. For hearing loss and hearing loss related tinnitus I am betting on FX-322 working though as they are almost definitely inner ear problems.

 

[weab00]

All this talk of FX-322 not working for hyperacusis is making me nervous.

 

[Lucifer]

All this talk of FX-322 not working for hyperacusis is making me nervous.

Me too man. I do hope it works for both pain and loudness hyperacusis though. It does make sense that once you restore hearing, such as OHCs, it should completely get rid of it.

 

[ASilverLight]

Yeah, I don't believe all this speculation is going to help anybody. Besides as I've mentioned previously, a lot of people have an acoustic shock or trauma without noxacusis - would nothing help then either even if all they have is tinnitus?

What about reactive tinnitus?

Thing is, we don't know. Even researchers cannot agree on why these things happen. It's all very poorly understood, and all this speculation of it not working for a lot of people on this site isn't going to do anyone any good.

Don't get me wrong, the discussions are interesting, but I've only been sticking around for the research forum and now even that makes me anxious and depressed.

Edit: maybe it would be a good idea to clarify whether you're only talking about it not working for any form of hyperacusis only, and share your thoughts on whether it could work for tinnitus caused by an acoustic shock.

 

[Diesel]

All this talk of FX-322 not working for hyperacusis is making me nervous.

Don't be. The problem with hyperacusis is that it's vague, general, catch-all for a lot of unrelated symptoms that doctors and researchers clearly don't agree on. Not to mention the classification challenge between pain (noxacusis) and "loudness" hyperacusis, and other symptoms that are added.

I think what might be helpful would be to simply list the exact known/understood symptoms related to hyperacusis and discuss how likely it is FX-322 may treat it.

For example, I believe that FX-322 will treat the following symptoms of hyperacusis that are likely of cochlear origin by regenerating IHC/OHC:

- "Loudness" or central gain
- Recruitment
- Distortion
- Sound sensitivity related to specific frequencies

May help treat, may not fix completely:

- Sound sensitivity pain of a cochlear origin
- Middle ear pain
- Localized pain around ear

It would be great to see someone on here that is more knowledgeable than I on the subject break it down in simple terms. (@100Hz)

Hopefully the outcome of these drugs results in a better classification of these symptoms.

 

[Jurger]

Frequency will be participating in a couple of upcoming conferences.


Frequency Therapeutics to Present at Upcoming Investor Conferences and Medical Meetings

Too bad the most interesting one won't be recorded.

 

[Joeseph Stope]

Well thank you so much 100 Hz for your excellent post. I had been having this uneasy feeling of the "herd instinct" placing all it's hopes in one basket. Don't get me wrong. I will be as happy as the next person if FX-322 can even reduce my tinnitus. But from what you've been discussing it looks like there may not be one single switch to turn back onto "silent mode".

But I have confidence that the new research will be able to do a lot. Karp and Langer seem to be like the innovators/entrepreneurs of old who trailblaze new ways of thinking and doing things by bringing in some real existing medicine. Academic papers are absolutely necessary for the knowledge base, but there are so few initiatives that spring forth.

For that matter, all that knowledge and research that went into Regain (was it called?), the British-Dutch-German consortium, I hope it just doesn't gather dust somewhere, that it can be put to use in the next thrusts.

 

[100Hz]

Don't worry too much about my own thinking behind it @weab00, because that's all it is, just my brain working OT. I really don't want to make anyone worried more than they should be about this. I'll post about this topic one last time on the Frequency Therapeutics thread and then maybe leave it at that.

I've had nagging doubts about FX-322 helping my noxacusis from the start (I'm talking about acoustic shock induced noxacusis). I go through periods where I get confident about Frequency Therapeutics, Otonomy, Hough but then I start dissecting it again and wondering if they really could be the answer though. I'm the type of person who would rather know why something was broken and how it was broken even if that meant knowing that the upcoming drugs were not going to work, instead of hanging onto these drugs that are not designed, being trialed for, or even barely mentioned for off label use for acoustic shock noxacusis. I'd love it if it could finally be worked out what caused it because then the research would be able to go full speed in the right direction and I think that would be 10X more valuable to us. These drugs could still be a couple of years away anyway at best so it might as well be dug into in the meantime.

I'm not just nay-saying or rubbishing anything and everything I hear, I desperately want something to work I'm just trying to think logically about it. I never intended to even get involved in the fx discussion but it just seemed to be going that way so I joined in. All I did was read that paper enough times to understand the logic of it and then map my own symptoms to it and I have to say, it's feasible. I'd urge anyone with acoustic shock noxacusis to do the same and then compare notes.

@ASilverLight, yes, I think that's correct, I understand acoustic shock can be so mild that people don't really know they've had one and get little to no symptoms from it. With regards to getting tinnitus from one but not noxacusis, the paper doesn't mention this specifically but does suggest a few possibilities about tinnitus, one being OHC related and one being the cochlear nucleus. This one below however I find the most interesting based on how it fits in with everything else I think could be possible from that paper.

Tinnitus that follows an acoustic trauma has been reported to fluctuate over time, in close correlation with tingling in the ear and otalgia. We have suggested that pain in the ear results from TGN activation due to TTM overload and injury. Interestingly, the TGN innervates the cochlea and the vestibular labyrinth: the blood vessels around the spiral modiolus, the stria vascularis, and the dark cell region of the cristae ampullaris. The action of TGN on the inner ear may contribute to generating tinnitus or modulate tinnitus loudness.

So according to this paper the cochlea is also innervated by the trigeminal nerve. The same nerve that innervates the tensor tympani, the mid ear mucosa, outer ear drum, and all of the facial muscles that seem to suffer delayed pain that I mentioned previously. So the cochlea is connected as well to all these significant muscles etc. and its been suggested in this case that the tinnitus is as a result maybe not of anything inside the cochlea, but instead as a result of the mid ear damage. I do guess possibly there would need to have been some preexisting tinnitus in this case though if it was modulating it, however it does state that it could actually generate it.

The way I read this then is, imagine a setback producing inflammation in the mid ear and then affecting everything it typically affects on the TGN. The inflammation causing the facial pain and the tinnitus according to this are effectively being regulated by the same source of inflammation, hence below. (I have this same symptom. My tinnitus spikes with the delayed pain, and then settles as the pain settles).

Tinnitus that follows an acoustic trauma has been reported to fluctuate over time, in close correlation with tingling in the ear and otalgia.

@Diesel, I think that's right.

I'd be skeptical for a complete fix for these from cochlea regen meds, probably something though:
Acoustic trauma induced noxacusis
Acoustic trauma induced tinnitus
Acoustic trauma induced ongoing setbacks
Acoustic trauma induced TTTS

But these I'd be really hopeful about:
Cochlea damage induced noxacusis (OHC damage)?
Cochlea damage induced hearing loss
Cochlea damage induced tinnitus
Recruitment (I don't know much about this but I believe it's hair cell related, isn't it?)

And as you say, once these drugs hopefully get released they will work for some conditions and if not, at least start a process of elimination of what doesn't work for other conditions.

 

[serendipity1996]

Yes that's the trouble with it, so much speculation.

Humor me for one minute, I'll throw a wild hypothesis out there without going into too much detail.

There is zero significant cochlea damage after the acoustic shock, if any. The acoustic shock caused the symptoms cluster in the mid ear and it is now the damaged/highly sensitive/high emotional response/etc. affected mid ear that is causing all of the problems, the delayed pain, and the 'feeling' that noise is hurting the inner ear when in fact it isn't. In effect sound is reaching the unaffacted cochlea but is going through a highly dysfunctional, misfiring, erratic, nerve sensitizing middle ear minefield to get there leaving a trail of inflammation in its wake which is presenting the illusion that the cochlea is the problem.

One quick way this might be substantiated to some degree is say someone had a life of normal noise (both ears received the same over the years). One day they both get the same loud noise. One gets an acoustic shock, from that day forward that ear experiences noxacusis with heightened sensitivity, delayed pain, etc. and the other one doesn't. The difference between the 2 ears is the acoustic shock so why point the finger at the cochlea? The other cochlea has had the same noise only no acoustic shock and remains unaffected.

Again just another speculation. For hearing loss and hearing loss related tinnitus I am betting on FX-322 working though as they are almost definitely inner ear problems.

One thing I'm trying to get my head around is how does this fit into the findings of Professor Anoveros from Northwestern that the response to noxious noise originates in the inner ear and not the middle ear or vestibule. This stood out to me, however:

"The response to noxious noise originates in the cochlea and not in other areas also stimulated by intense noise (middle ear and vestibule), as the response was absent in another type of mutant mice with selective cochlear degeneration but normal vestibular and somatosensory function."

So the middle-ear and vestibule can also be 'stimulated' by intense noise. Could it be possible that sub-noxious then, if it's not affecting the inner ear, could still stimulate the middle ear?

https://hyperacusisresearch.org/2016-aro-symposium-pain-hyperacusis/

 

[weab00]

I've read before that people who get hyperacusis are also more likely to have various forms of tendonitis in their body, since their body is more prone to inflammation in general. Anecdotally I can say that I got many forms of tendonitis when I used to run cross country, and ulnar nerve pain when I play the bass.

Anyone else notice similarly?

 

[ASilverLight]

Don't worry too much about my own thinking behind it @weab00, because that's all it is, just my brain working OT. I really don't want to make anyone worried more than they should be about this. I'll post about this topic one last time on the Frequency Therapeutics thread and then maybe leave it at that.

I've had nagging doubts about FX-322 helping my noxacusis from the start (I'm talking about acoustic shock induced noxacusis). I go through periods where I get confident about Frequency Therapeutics, Otonomy, Hough but then I start dissecting it again and wondering if they really could be the answer though. I'm the type of person who would rather know why something was broken and how it was broken even if that meant knowing that the upcoming drugs were not going to work, instead of hanging onto these drugs that are not designed, being trialed for, or even barely mentioned for off label use for acoustic shock noxacusis. I'd love it if it could finally be worked out what caused it because then the research would be able to go full speed in the right direction and I think that would be 10X more valuable to us. These drugs could still be a couple of years away anyway at best so it might as well be dug into in the meantime.

I'm not just nay-saying or rubbishing anything and everything I hear, I desperately want something to work I'm just trying to think logically about it. I never intended to even get involved in the fx discussion but it just seemed to be going that way so I joined in. All I did was read that paper enough times to understand the logic of it and then map my own symptoms to it and I have to say, it's feasible. I'd urge anyone with acoustic shock noxacusis to do the same and then compare notes.

@ASilverLight, yes, I think that's correct, I understand acoustic shock can be so mild that people don't really know they've had one and get little to no symptoms from it. With regards to getting tinnitus from one but not noxacusis, the paper doesn't mention this specifically but does suggest a few possibilities about tinnitus, one being OHC related and one being the cochlear nucleus. This one below however I find the most interesting based on how it fits in with everything else I think could be possible from that paper.

Tinnitus that follows an acoustic trauma has been reported to fluctuate over time, in close correlation with tingling in the ear and otalgia. We have suggested that pain in the ear results from TGN activation due to TTM overload and injury. Interestingly, the TGN innervates the cochlea and the vestibular labyrinth: the blood vessels around the spiral modiolus, the stria vascularis, and the dark cell region of the cristae ampullaris. The action of TGN on the inner ear may contribute to generating tinnitus or modulate tinnitus loudness.

So according to this paper the cochlea is also innervated by the trigeminal nerve. The same nerve that innervates the tensor tympani, the mid ear mucosa, outer ear drum, and all of the facial muscles that seem to suffer delayed pain that I mentioned previously. So the cochlea is connected as well to all these significant muscles etc. and its been suggested in this case that the tinnitus is as a result maybe not of anything inside the cochlea, but instead as a result of the mid ear damage. I do guess possibly there would need to have been some preexisting tinnitus in this case though if it was modulating it, however it does state that it could actually generate it.

The way I read this then is, imagine a setback producing inflammation in the mid ear and then affecting everything it typically affects on the TGN. The inflammation causing the facial pain and the tinnitus according to this are effectively being regulated by the same source of inflammation, hence below. (I have this same symptom. My tinnitus spikes with the delayed pain, and then settles as the pain settles).

Tinnitus that follows an acoustic trauma has been reported to fluctuate over time, in close correlation with tingling in the ear and otalgia.

@Diesel, I think that's right.

I'd be skeptical for a complete fix for these from cochlea regen meds, probably something though:
Acoustic trauma induced noxacusis
Acoustic trauma induced tinnitus
Acoustic trauma induced ongoing setbacks
Acoustic trauma induced TTTS

But these I'd be really hopeful about:
Cochlea damage induced noxacusis (OHC damage)?
Cochlea damage induced hearing loss
Cochlea damage induced tinnitus
Recruitment (I don't know much about this but I believe it's hair cell related, isn't it?)

And as you say, once these drugs hopefully get released they will work for some conditions and if not, at least start a process of elimination of what doesn't work for other conditions.

What then "bugs" me about this, is that for some tinnitus is all there is. No tingling, no pain, no feelings of fullness or anything at all. Just tinnitus.

Which makes me wonder whether that really may just be some kind of hearing damage, or simply a result of a brain going into some sort of hyper-viligant mode. Honestly though, I'm certain that even acoustic shocks or traumas cause some hearing loss which may be the very source for ongoing damage after all. Now I'm just speculating myself though.

I suffered a very, very mild trauma that I didn't register as such but could have been one, but suffered no pain or hyperacusis at any point as a result. I only got tinnitus, but not until I had major panic attacks over a different issue... and this was 2 weeks later. Which again brings me to a brain theory rather than middle ear damage.

My tinnitus does fluctuate (randomly, regardless of sound) but no pain whatsoever. Definitely no facial pain.

It sucks we know so little. I just hope you're wrong and that this will help people with acoustic traumas too. I feel like those with no other issues may be more at luck, but who knows.

 

[tommyd87]

Yes that's the trouble with it, so much speculation.

Humor me for one minute, I'll throw a wild hypothesis out there without going into too much detail.

There is zero significant cochlea damage after the acoustic shock, if any. The acoustic shock caused the symptoms cluster in the mid ear and it is now the damaged/highly sensitive/high emotional response/etc. affected mid ear that is causing all of the problems, the delayed pain, and the 'feeling' that noise is hurting the inner ear when in fact it isn't. In effect sound is reaching the unaffacted cochlea but is going through a highly dysfunctional, misfiring, erratic, nerve sensitizing middle ear minefield to get there leaving a trail of inflammation in its wake which is presenting the illusion that the cochlea is the problem.

One quick way this might be substantiated to some degree is say someone had a life of normal noise (both ears received the same over the years). One day they both get the same loud noise. One gets an acoustic shock , from that day forward that ear experiences noxacusis with heightened sensitivity, delayed pain, etc. and the other one doesn't. The difference between the 2 ears is the acoustic shock so why point the finger at the cochlea? The other cochlea has had the same noise and is fine plus has had no acoustic shock.

Again just another speculation. For hearing loss and hearing loss related tinnitus I am betting on FX-322 working though as they are almost definitely inner ear problems.

That tends to be an appropriate hypothesis. Having a look at what you are actually saying, I would suggest that could either be possible or could be hopefully investigated. Probably looking at what we are seeing with the medication thus far and looking at what it is supposed to fix, I reckon that it will be possible to investigate these types of conditions based on the outcomes after using FX-322 or similar medicine.

I really reckon that the medicine will be the breakthrough for actually learning about the ear and hearing. Have had a look at some of the comments even in relation to the medicine from supposed super gurus and their comments have been vague, confusing and even misleading. Probably the favourite comment had to be that there was a certain group who when asked about hearing issues said that hearing loss has a number of potential causes and proceeded to write a short piece of non-specific and irrelevant information. It would have been better if they had just said we cannot know or we cannot explain it because that is exactly how the message of their comment came across after picking it apart.

At this stage I seriously think that the medicine most likely will alter what a few of the supposed experts have thought about the ear or have been telling us in regards to hearing loss.

Well thank you so much 100 Hz for your excellent post. I had been having this uneasy feeling of the "herd instinct" placing all it's hopes in one basket. Don't get me wrong. I will be as happy as the next person if FX-322 can even reduce my tinnitus. But from what you've been discussing it looks like there may not be one single switch to turn back onto "silent mode".

But I have confidence that the new research will be able to do a lot. Karp and Langer seem to be like the innovators/entrepreneurs of old who trailblaze new ways of thinking and doing things by bringing in some real existing medicine. Academic papers are absolutely necessary for the knowledge base, but there are so few initiatives that spring forth.

For that matter, all that knowledge and research that went into Regain (was it called?), the British-Dutch-German consortium, I hope it just doesn't gather dust somewhere, that it can be put to use in the next thrusts.

I think that @100Hz was just being analytical and also putting forward a number of hypotheses about actually possible situations which could possibly happen as a result of the treatment.

Most certainly he will tell me if I am wrong lol.

 

[Diesel]

Don't worry too much about my own thinking behind it @weab00, because that's all it is, just my brain working OT. I really don't want to make anyone worried more than they should be about this. I'll post about this topic one last time on the Frequency Therapeutics thread and then maybe leave it at that.

I've had nagging doubts about FX-322 helping my noxacusis from the start (I'm talking about acoustic shock induced noxacusis). I go through periods where I get confident about Frequency Therapeutics, Otonomy, Hough but then I start dissecting it again and wondering if they really could be the answer though. I'm the type of person who would rather know why something was broken and how it was broken even if that meant knowing that the upcoming drugs were not going to work, instead of hanging onto these drugs that are not designed, being trialed for, or even barely mentioned for off label use for acoustic shock noxacusis. I'd love it if it could finally be worked out what caused it because then the research would be able to go full speed in the right direction and I think that would be 10X more valuable to us. These drugs could still be a couple of years away anyway at best so it might as well be dug into in the meantime.

I'm not just nay-saying or rubbishing anything and everything I hear, I desperately want something to work I'm just trying to think logically about it. I never intended to even get involved in the fx discussion but it just seemed to be going that way so I joined in. All I did was read that paper enough times to understand the logic of it and then map my own symptoms to it and I have to say, it's feasible. I'd urge anyone with acoustic shock noxacusis to do the same and then compare notes.

@ASilverLight, yes, I think that's correct, I understand acoustic shock can be so mild that people don't really know they've had one and get little to no symptoms from it. With regards to getting tinnitus from one but not noxacusis, the paper doesn't mention this specifically but does suggest a few possibilities about tinnitus, one being OHC related and one being the cochlear nucleus. This one below however I find the most interesting based on how it fits in with everything else I think could be possible from that paper.

Tinnitus that follows an acoustic trauma has been reported to fluctuate over time, in close correlation with tingling in the ear and otalgia. We have suggested that pain in the ear results from TGN activation due to TTM overload and injury. Interestingly, the TGN innervates the cochlea and the vestibular labyrinth: the blood vessels around the spiral modiolus, the stria vascularis, and the dark cell region of the cristae ampullaris. The action of TGN on the inner ear may contribute to generating tinnitus or modulate tinnitus loudness.

So according to this paper the cochlea is also innervated by the trigeminal nerve. The same nerve that innervates the tensor tympani, the mid ear mucosa, outer ear drum, and all of the facial muscles that seem to suffer delayed pain that I mentioned previously. So the cochlea is connected as well to all these significant muscles etc. and its been suggested in this case that the tinnitus is as a result maybe not of anything inside the cochlea, but instead as a result of the mid ear damage. I do guess possibly there would need to have been some preexisting tinnitus in this case though if it was modulating it, however it does state that it could actually generate it.

The way I read this then is, imagine a setback producing inflammation in the mid ear and then affecting everything it typically affects on the TGN. The inflammation causing the facial pain and the tinnitus according to this are effectively being regulated by the same source of inflammation, hence below. (I have this same symptom. My tinnitus spikes with the delayed pain, and then settles as the pain settles).

Tinnitus that follows an acoustic trauma has been reported to fluctuate over time, in close correlation with tingling in the ear and otalgia.

@Diesel, I think that's right.

I'd be skeptical for a complete fix for these from cochlea regen meds, probably something though:
Acoustic trauma induced noxacusis
Acoustic trauma induced tinnitus
Acoustic trauma induced ongoing setbacks
Acoustic trauma induced TTTS

But these I'd be really hopeful about:
Cochlea damage induced noxacusis (OHC damage)?
Cochlea damage induced hearing loss
Cochlea damage induced tinnitus
Recruitment (I don't know much about this but I believe it's hair cell related, isn't it?)

And as you say, once these drugs hopefully get released they will work for some conditions and if not, at least start a process of elimination of what doesn't work for other conditions.

Thank you for the detailed response. I have one question though, the one that stands out to me is Acoustic Trauma Induced Tinnitus.

It stands to reason that there is a fairly good correlation between NIHL/SNHL resulting in the loss of a patient's hair cells and the prevalence of their tone-matched tinnitus. This is why many have speculated that Frequency Therapeutics is testing for UHF hearing and tinnitus. Also, the claim of participant testimonials in the Phase 1/2 having improved tinnitus seems to reinforce this. 1 dose of FX-322 likely improved UHF hearing, and may have reduced the tinnitus symptom. We're making the presumption that the tinnitus is in the high range AND/OR improved signal to the auditory system made it quieter.

So, I am having trouble understanding how tinnitus produced from an acoustic trauma wouldn't be helped? The tinnitus is still a symptom of OHC/IHC loss as far as we know. This seems to be counter to what we have seen casually on these forums; in those that have had an acoustic trauma mentioned their tinnitus sound and hearing losses correlate.

Anecdotally speaking, this is the case for me as well. High frequency tinnitus is dominant, and I cannot hear above 12 kHz.

 

[serendipity1996]

Thank you for the detailed response. I have one question though, the one that stands out to me is Acoustic Trauma Induced Tinnitus.

It stands to reason that there is a fairly good correlation between NIHL/SNHL resulting in the loss of a patient's hair cells and the prevalence of their tone-matched tinnitus. This is why many have speculated that Frequency Therapeutics is testing for UHF hearing and tinnitus. Also, the claim of participant testimonials in the Phase 1/2 having improved tinnitus seems to reinforce this. 1 dose of FX-322 likely improved UHF hearing, and may have reduced the tinnitus symptom. We're making the presumption that the tinnitus is in the high range AND/OR improved signal to the auditory system made it quieter.

So, I am having trouble understanding how tinnitus produced from an acoustic trauma wouldn't be helped? The tinnitus is still a symptom of OHC/IHC loss as far as we know. This seems to be counter to what we have seen casually on these forums; in those that have had an acoustic trauma mentioned their tinnitus sound and hearing losses correlate.

Anecdotally speaking, this is the case for me as well. High frequency tinnitus is dominant, and I cannot hear above 12 kHz.

Anecdotally speaking, in my case certain frequencies (phone/laptop) cause difficulty for me in that they trigger reactive tinnitus, delayed facial pain, and overall these frequencies just sound very abrasive and piercing. This has kind of improved but not totally.

This leads me to believe that the culprit is hearing loss at certain frequencies which triggers this whole constellation of symptoms. The sound quality also sounds kind of different - flat and sort of distorted which again makes me suspect that there is an underlying hearing loss at the root of this.

 

[ASilverLight]

Thank you for the detailed response. I have one question though, the one that stands out to me is Acoustic Trauma Induced Tinnitus.

It stands to reason that there is a fairly good correlation between NIHL/SNHL resulting in the loss of a patient's hair cells and the prevalence of their tone-matched tinnitus. This is why many have speculated that Frequency Therapeutics is testing for UHF hearing and tinnitus. Also, the claim of participant testimonials in the Phase 1/2 having improved tinnitus seems to reinforce this. 1 dose of FX-322 likely improved UHF hearing, and may have reduced the tinnitus symptom. We're making the presumption that the tinnitus is in the high range AND/OR improved signal to the auditory system made it quieter.

So, I am having trouble understanding how tinnitus produced from an acoustic trauma wouldn't be helped? The tinnitus is still a symptom of OHC/IHC loss as far as we know. This seems to be counter to what we have seen casually on these forums; in those that have had an acoustic trauma mentioned their tinnitus sound and hearing losses correlate.

Yeah, this is what I got really confused about, too. I do see how perhaps muscles etc can influence the fluctuation of tinnitus, but I fail to see how middle ear damage alone is entirely responsible for tinnitus, as tinnitus is primarily a reaction to hearing loss or disruption. Although I don't know about my UHF hearing (it seems fine based on laptop tests, but of course that does not paint a good picture), my standard audiogram is perfect - yet I still have tinnitus.

If acoustic shock/trauma induced tinnitus is supposedly caused by inflammation triggering a cluster of symptoms that people may not have (eg noxacusis, nerve pain) I fail to see how tinnitus is then not mostly caused by UHF losses (or synapses!)

Personally I can see it true to be ongoing inflammatory processes - but triggered by some kind of hearing damage. Which then leads me to believe that curing the hearing loss should help with the inflammation and this lower tinnitus, too.

Again, it's all just speculation from all of us, and it makes me very nervous sometimes. I partially blame a very mild noise trauma now (it was an alarm I was exposed to for all of two seconds, around 100 dB at the very most) but I think it was ultimately triggered by a combination of that and extreme anxiety/stress with perhaps some influence from my neck.

I think that noxacusis may very well be an issue within the middle ear and its muscles, but I just don't see how tinnitus becomes part of that lest there is hearing loss - keep in mind that many people only get tinnitus and no other symptoms, and loud and sudden noises can and often most definitely do cause some kind of damage to the hearing.

 

[xyz]

Yes that's the trouble with it, so much speculation.

Humor me for one minute, I'll throw a wild hypothesis out there without going into too much detail.

There is zero significant cochlea damage after the acoustic shock, if any. The acoustic shock caused the symptoms cluster in the mid ear and it is now the damaged/highly sensitive/high emotional response/etc. affected mid ear that is causing all of the problems, the delayed pain, and the 'feeling' that noise is hurting the inner ear when in fact it isn't. In effect sound is reaching the unaffacted cochlea but is going through a highly dysfunctional, misfiring, erratic, nerve sensitizing middle ear minefield to get there leaving a trail of inflammation in its wake which is presenting the illusion that the cochlea is the problem.

One quick way this might be substantiated to some degree is say someone had a life of normal noise (both ears received the same over the years). One day they both get the same loud noise. One gets an acoustic shock, from that day forward that ear experiences noxacusis with heightened sensitivity, delayed pain, etc. and the other one doesn't. The difference between the 2 ears is the acoustic shock so why point the finger at the cochlea? The other cochlea has had the same noise only no acoustic shock and remains unaffected.

Again just another speculation. For hearing loss and hearing loss related tinnitus I am betting on FX-322 working though as they are almost definitely inner ear problems.

Read the paper @sssing has linked here:

I remember this article about middle ear muscle reflex changing after cochlear damage by Liberman. It says that when there's damage in the inner hair cells, the middle ear muscle reflex is affected. So I think yes, all the ear structures are interrelated. Before I had this bad tinnitus and hyperacusis, my ear muscle would keep fluttering. I just thought it was due to temperature change. Now, looking back, I think it was a sign of damage being done. If only I knew earlier, I would have been more careful with noise.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244259/

Acoustic shock induces inner ear damage which leads to middle ear problems. I don't think the middle ear goes crazy on its own.

 

[NewLionel]

Anecdotally speaking, in my case certain frequencies (phone/laptop) cause difficulty for me in that they trigger reactive tinnitus, delayed facial pain, and overall these frequencies just sound very abrasive and piercing. This has kind of improved but not totally.

This leads me to believe that the culprit is hearing loss at certain frequencies which triggers this whole constellation of symptoms. The sound quality also sounds kind of different - flat and sort of distorted which again makes me suspect that there is an underlying hearing loss at the root of this.

I have a similar problem, things sounding thin/abrasive. But there can be a huge variance day to day, same with tinnitus/hyperacusis... If it was hearing loss, which is permanent, why would there be so much variance? Would inflammation of some sort not be more likely?

 

[Lucifer]

Anecdotally speaking, in my case certain frequencies (phone/laptop) cause difficulty for me in that they trigger reactive tinnitus, delayed facial pain, and overall these frequencies just sound very abrasive and piercing. This has kind of improved but not totally.

This leads me to believe that the culprit is hearing loss at certain frequencies which triggers this whole constellation of symptoms. The sound quality also sounds kind of different - flat and sort of distorted which again makes me suspect that there is an underlying hearing loss at the root of this.

This is why I believe once we can restore hearing input this should resolve issues such as tinnitus, pain and loudness hyperacusis.

 

[serendipity1996]

I have a similar problem, things sounding thin/abrasive. But there can be a huge variance day to day, same with tinnitus/hyperacusis... If it was hearing loss, which is permanent, why would there be so much variance? Would inflammation of some sort not be more likely?

I think it could definitely be inflammation - perhaps it fluctuates day to day. It could depend on how far out you are from your acoustic trauma or whatever caused the damage.

 

[GBB]

Dumb question - I believe Frequency Therapeutics said when the hair cells were restored they reconnected to synapses, meaning this should also help with synaptopathy.

However, I've also read once disconnected that the synapses die over days/weeks/months. If you get an injection then several years after an acoustic trauma, will the synapses also regenerate, or are you capped in terms of your healing potential because they are already dead?

 

[Diesel]

Dumb question - I believe Frequency Therapeutics said when the hair cells were restored they reconnected to synapses, meaning this should also help with synaptopathy.

However, I've also read once disconnected that the synapses die over days/weeks/months. If you get an injection then several years after an acoustic trauma, will the synapses also regenerate, or are you capped in terms of your healing potential because they are already dead?

It will help with synaptopathy where a damaged or missing outer or inner cell is regenerated. The new OHC/IHC is reconnected to the proper synapse. As nature intended.

Chris Loose once responded to a question regarding the therapeutic window for FX-322 to work. He mentioned that participants in the Phase 1/2 that had hearing loss for years and years, implying that some were much older, still saw a benefit since their progenitor cells were still in place.

So far no mention of a therapeutic window has been explicit anywhere with FX-323. At this point frequency is recruiting people in the Phase 2A that have endured notably worse damage/wear to hearing than normal.

It is likely as long as you're not at profound level of hearing loss, you should see a benefit.

 

[FGG]

Dumb question - I believe Frequency Therapeutics said when the hair cells were restored they reconnected to synapses, meaning this should also help with synaptopathy.

However, I've also read once disconnected that the synapses die over days/weeks/months. If you get an injection then several years after an acoustic trauma, will the synapses also regenerate, or are you capped in terms of your healing potential because they are already dead?

They have said that in cases where the hair cell is also destroyed, they will regrow synapses.

There are other companies working on treating synaptopathy in cases where hair cells are not lost: Otonomy, Pipeline Therapeutics, Hough Ear Institute.

 

[tomytl]

It will help with synaptopathy where a damaged or missing outer or inner cell is regenerated. The new OHC/IHC is reconnected to the proper synapse. As nature intended.

Chris Loose once responded to a question regarding the therapeutic window for FX-322 to work. He mentioned that participants in the Phase 1/2 that had hearing loss for years and years, implying that some were much older, still saw a benefit since their progenitor cells were still in place.

So far no mention of a therapeutic window has been explicit anywhere with FX-323. At this point frequency is recruiting people in the Phase 2A that have endured notably worse damage/wear to hearing than normal.

It is likely as long as you're not at profound level of hearing loss, you should see a benefit.

Are OHCs also expected to regrow?

These are the amplifiers, so it would be really awesome if there was the possibility of regrowth.

 

[serendipity1996]

Are OHCs also expected to regrow?

Yes both OHCs and IHCs.

 

[Remjii79]

If one has profound hearing loss in the >4 kHz ranges, but only mild to severe hearing loss in the <4 kHz ranges, will FX-322 work for the <4 kHz ranges, assuming they can deliver the drug?

 

[100Hz]

So, I am having trouble understanding how tinnitus produced from an acoustic trauma wouldn't be helped?

Great point, you're right, I agree on that. FX-322 could in theory fix the tinnitus regardless of how it started (pre existing or acoustic shock). Although subsequent setbacks originating in the mid ear causing fresh TGN inflammation could generate that tinnitus again or other problems in the cochlea requiring further FX-322. Let's say FX-322 works though then that would be amazing in itself because in theory you'd know you could fix the cochlea over and over (as long as you had the support cells to do it), and then if the problem of setbacks and delayed facial pain etc. remained, subsequently causing the tinnitus etc. to return each time, then that could help to highlight the real cause of the problems in the mid ear and put research for it on the right track.

I think that noxacusis may very well be an issue within the middle ear and its muscles, but I just don't see how tinnitus becomes part of that lest there is hearing loss - keep in mind that many people only get tinnitus and no other symptoms, and loud and sudden noises can and often most definitely do cause some kind of damage to the hearing.

I agree that it's so unlikely for there to be zero hearing loss or tinnitus, whether it was present already or as a result of the acoustic shock. My hypothesis a few posts back was at one end of the spectrum putting all the emphasis on the mid ear being damaged but not the inner ear, but there could be any number of variations in between. The chance that you've had an acoustic shock strong enough to cause some hearing loss and tinnitus, yet not strong enough to sensitize the TGN or cause any significant mid ear damage I'd say is more than possible and could explain your particular symptoms and make FX-322 perfect for you. I still think the above reply to Diesel applies though if you are now susceptible to acoustic shocks or setbacks. Does your tinnitus fluctuate or is it constant? If it fluctuates does it do so in parallel with any other symptoms? Because if it does and you can pin the other symptoms down to a possible inflammatory response it could tell you if your tinnitus is being modulated from outside the cochlea.

This hypothesis is assuming the mid ear is the trigger for setbacks and pain and even cochlea damage, that's the whole point of it, propose something and then try and smash the theory. The 'what triggers what' theory is a different hypothesis I'm trying to get my head around, it depends on so many things. But for this current theory, if an acoustic shock does damage the mid ear and the cochlea together but FX-322 fixes only the cochlea, yet the setbacks repeatedly damage the cochlea again and again requiring more and more FX-322 then the mid ear surely needs to be fixed as well. The big problem and the reason I'm digging so much into this though, and I'm sure I speak for a lot of acoustic shock noxacusis sufferers, is that the part of this I really want to fix is the constant setbacks and months of crippling facial pain over and above anything else. And I believe this requires a mid ear related fix.

@tommyd87, thanks, yes that's all it is, just a theory to run with. I don't particularly believe it's true or untrue. I'm just questioning it with everything I can throw at it until it crumbles lol.

"The response to noxious noise originates in the cochlea and not in other areas also stimulated by intense noise (middle ear and vestibule), as the response was absent in another type of mutant mice with selective cochlear degeneration but normal vestibular and somatosensory function."

So the middle-ear and vestibule can also be 'stimulated' by intense noise. Could it be possible that sub-noxious then, if it's not affecting the inner ear, could still stimulate the middle ear?

I think I get what you're asking but it could be 2 different questions. Your first quote could point to the possibility that the cochlea is being damaged first and sending some kind of response to the mid ear that is then also damaging itself due to acoustic shock, is that right? If that's the question then I'd say that whether FX-322 could fix both depends on if there is now a heightened state of alert somewhere in the nervous system that has been turned on like a switch that the the mid ear will continue to respond to even if the cochlea gets fixed. Unless the cochlea can be fixed and then the mid ear 're-learnt' it's normal response over time. I'm trying to work on some other concepts to do with what is triggering what.

But if this is your question, 'So the middle-ear and vestibule can also be 'stimulated' by intense noise. Could it be possible that sub-noxious then, if it's not affecting the inner ear, could still stimulate the middle ear?' I'd say definitely yes because that acoustic shock paper goes into so much detail about how the tensor tympani can severely damage itself causing all the TGN sensitization etc. upon hearing damaging (noxious) noise. And I think to answer your question, the important thing I pick up on here is that the tensor tympani is responding to what it feels is noxious noise (whether unreasonably so or not) and therefore causing the devastating mid ear symptoms cluster regardless of how noxious the noise actually is. This is why I think sometimes we get lowered tolerance. The noise that the mid ear thinks is so noxious and is responding so dramatically to due to some kind of heightened response (causing all kinds of inflammatory responses that ARE causing pain) actually in fact possess zero risk of damaging the cochlea at all.

@xyz, thanks, I'll read that, that looks like it going to take a while to understand.