Frequency Therapeutics — Hearing Loss Regeneration

[Mr. G]

Reading the news it would appear trouble on the Frequency Therapeutics front. News says they are being investigated for possible false or misleading statements. I really hope this shakes out to be on the up and up in the long run. But yes likely some stressed investors.

 

[Zugzug]

I think this is way more multi factorial than that (as medicine tends to be).

For instance, you could have low word scores and a lot of IHC loss and for whatever reason, it be concentrated below 6 kHz. I would actually like to see that individuals' audiogram because it would make sense for them to be weighted towards more losses towards the apex than the responders.

To make this even more complicated, synapse loss only tends to come before IHC loss with gradual hearing loss. There was one researcher who showed that there are certain types of acute noise-induced losses that only damage IHCs (a loud 4000 Hz noise specifically if i remember correctly), some that only damage OHCs and some that are mixed and it depends on frequency and duration.

@HootOwl has that study and maybe she can repost it. So, there isn't even a uniform way that people lose hair cells.

I noted before that @Diesel's paper showed that losing one row of OHCs only results in a 5-10 dB change. If the rat study holds true for people that's another potential reason we didn't see significant audiogram changes (i still think we would see a lot more 5-10 dB changes unless there was also an IHC preference unless they did see that in individuals but it doesn't exceed the allowed test/retest variation?). The individual audiograms matched to word scores would help so much.

I don't understand what you mean by only helping IHCs a little bit. Unless you mean not across the whole cochlea and I agree with that.

As far as your own hyperacusis, when they say "auditory nerve fibers" in those studies, they mean the neurites regress because they are no longer synapsed (aka synaptopathy), it doesn't mean you will go deaf.

So I guess here's where I disagree with you two. We agree that there's not a great diagnostic test to determine where the IHC loss is. But is it really not well-correlated with the location of OHC loss? I know you have alluded to this with the one patient who didn't respond to WR. But all it would take is one patient who responded to WR with ~normal PTA in >= 8 kHz to wonder what was going on. Did they really have random IHC loss and no OHC loss in those ranges? I guess it's possible, but it's so easy to cast doubts on this with a few people.

Re: 5-10 dB OHC changes: That was in the third row. It's hard for me to believe that the people who improved some in PTA and considerably in WR saw improvements in IHC and third row OHC. It makes a lot more sense to me that it would be IHC and 1st row of OHC.

Maybe I am misinterpreting the study, but I took it as more than just "rats can lose a row of OHC and only see 5-10 dB changes in thresholds." I took it as the order also mattering. I guess we don't know for sure. They performed the experiment with styrene and it was convenient because it enabled them to work outward to inward, being sure that only OHC were destroyed. It would be of interest to see an experiment where only the first row of OHC were destroyed.

 

[FGG]

Reading the news it would appear trouble on the Frequency Therapeutics front. News says they are being investigated for possible false or misleading statements. I really hope this shakes out to be on the up and up in the long run. But yes likely some stressed investors.

They aren't being "investigated", law firms (and the ones involved are biotech frequent flyers) are putting out ads looking for plaintiffs as they do whenever biotech shares drop significantly.

Even if they do find some plaintiffs willing to hop on board, odds are pretty low it would go anywhere:

Life Sciences Companies: Frequent Securities Suits Frequently Dismissed

 

[Diesel]

So I guess here's where I disagree with you two. We agree that there's not a great diagnostic test to determine where the IHC loss is. But is it really not well-correlated with the location of OHC loss? I know you have alluded to this with the one patient who didn't respond to WR. But all it would take is one patient who responded to WR with ~normal PTA in >= 8 kHz to wonder what was going on. Did they really have random IHC loss and no OHC loss in those ranges? I guess it's possible, but it's so easy to cast doubts on this with a few people.

Re: 5-10 dB OHC changes: That was in the third row. It's hard for me to believe that the people who improved some in PTA and considerably in WR saw improvements in IHC and third row OHC. It makes a lot more sense to me that it would be IHC and 1st row of OHC.

Maybe I am misinterpreting the study, but I took it as more than just "rats can lose a row of OHC and only see 5-10 dB changes in thresholds." I took it as the order also mattering. I guess we don't know for sure. They performed the experiment with styrene and it was convenient because it enabled them to work outward to inward, being sure that only OHC were destroyed. It would be of interest to see an experiment where only the first row of OHC were destroyed.

Let me draw up a diagram... brb.

 

[RingingBrother]

I wonder how much faster all future trials will wrap up if they're going to be single dose from now on? Hopefully this means we'll get it sooner.

 

[FGG]

So I guess here's where I disagree with you two. We agree that there's not a great diagnostic test to determine where the IHC loss is. But is it really not well-correlated with the location of OHC loss? I know you have alluded to this with the one patient who didn't respond to WR. But all it would take is one patient who responded to WR with ~normal PTA in >= 8 kHz to wonder what was going on. Did they really have random IHC loss and no OHC loss in those ranges? I guess it's possible, but it's so easy to cast doubts on this with a few people.

Re: 5-10 dB OHC changes: That was in the third row. It's hard for me to believe that the people who improved some in PTA and considerably in WR saw improvements in IHC and third row OHC. It makes a lot more sense to me that it would be IHC and 1st row of OHC.

Maybe I am misinterpreting the study, but I took it as more than just "rats can lose a row of OHC and only see 5-10 dB changes in thresholds." I took it as the order also mattering. I guess we don't know for sure. They performed the experiment with styrene and it was convenient because it enabled them to work outward to inward, being sure that only OHC were destroyed. It would be of interest to see an experiment where only the first row of OHC were destroyed.

I look forward to @Diesel's drawing.

Yes you can have IHC loss and OHC loss in different places as well as synaptopathy in different places. It depends entirely on the cause. With noise induced loss especially, different types of noise produce different lesions. Hopefully, @HootOwl still has that study handy because I think it would help show this better.

I truly don't know what you mean by "wouldn't the improvements happen in the 1st row vs the 3rd?" I don't think the 5-10 dB improvements were necessarily because it was 3rd row, that just happened to be how Styrene poisoned cells. I interpreted that to be a function of a certain amount of redundancy in OHCs, not positional effect. As an aside, why would you expect the first row of OHCs to regrow 1st by the way? I wasn't following your logic.

 

[HootOwl]

Hopefully, @HootOwl still has that study handy because I think it would help show this better.

Yep, here they be.

Relation of focal hair-cell lesions to noise-exposure parameters from a 4- or a 0.5-kHz octave band of noise

Distribution of focal lesions in the chinchilla organ of Corti following exposure to a 4-kHz or a 0.5-kHz octave band of noise

I believe the researcher wanted to continue with more experiments that would expand our understanding of how different frequencies and durations of noise exposure impacts the different structures of the cochlea, but they have unfortunately passed away.

 

[Zugzug]

I look forward to @Diesel's drawing.

Yes you can have IHC loss and OHC loss in different places as well as synaptopathy in different places. It depends entirely on the cause. With noise induced loss especially, different types of noise produce different lesions. Hopefully, @HootOwl still has that study handy because I think it would help show this better.

I truly don't know what you mean by "wouldn't the improvements happen in the 1st row vs the 3rd?" I don't think the 5-10 dB improvements were necessarily because it was 3rd row, that just happened to be how Styrene poisoned cells. I interpreted that to be a function of a certain amount of redundancy in OHCs, not positional effect. As an aside, why would you expect the first row of OHCs to regrow 1st by the way? I wasn't following your logic.

Let me restate my opinions in a better spirit of what I meant. You're right that I have no idea or reason to believe that the 1st row of OHC would be the one to regrow.

What I really am doing is creating immediate questions about these theories. We need to be precise about what was demonstrated. The study showed that third row OHC poisoning leads to only 5-10 dB shifts. A theory is that the difference between rows is negligible and that high redundancy was what was demonstrated. How do we know it wasn't more? How do we know the attached Figure 1 would reproduce with other orders? From this graph, it appears like losing 1/3 of OHC does little, losing 2/3 does a lot, and after that, it's basically the same thing. But wouldn't the second row also have the most neighbors? It's position also causes it to have different force mechanics on the basilar membrane.

For example, in [1], they looked at a finite element model (which I don't understand) of the cross sections of gerbil cochlea. In particular, the goal of the study was to simulate the impact on basilar membrane displacement as a result of various forces, including outer hair cell amplification, and lack thereof, caused by noise trauma and ototoxicity. This study was based on the experiment in [2] on an actual gerbil.

Anyways, several things from [1] really stood out to me that offered alternative considerations to @Diesel's study on rats [3].

Main point: As was structured in [1], consider that for a given slice of the organ of corti, there are three rows of OHC: OHC-1, OHC-2, and OHC-3. Each one can either be A (active) or P (passive). Hence, one example is AAP to mean active, active, passive (this would be the case in the styrene experiment).

Anyways, in [1], they considered two cases. The first case was various levels of noise trauma. They assumed that noise trauma hits in the order of layer 1, layer 2, then layer 3. So we can have AAA (no trauma), then PAA, then PPA, then PPP (all destroyed).

Interestingly, for ototoxicity, they reversed these assumptions, just like in [3]. Hence, for ototoxicity, the order would go AAA (no ototoxicity), then AAP, then APP, then PPP (all destroyed).

To summarize a bunch of complicated calculations, the attached Figure 2 was generated in [1], measuring changes in BM displacement based on the state of the three rows, respectively. Importantly, note that in both cases (two subfigures in Figure 2), the bar graphs are unsurprisingly monotone decreasing, as obviously more passive rows leads to less BM displacement. But, if we look at case PAA versus case AAP, there is a difference.

Do I think I am proving anything? No. But my point is that the rows matter. Actually, in [1], they underscore my point in a straightforward way. This whole quote is in reference to @Diesel's study [3]:

Another experiment using styrene, which was orally dosed, showed CAP threshold shifts of 8, 34, and 32 dB with 35, 70, and 100% OHC losses from OHC-3 to OHC-1, respectively [21]. In this case, OHC loss from 35% to 70% had greater effects on the cochlear amplification than that of the first 35% or that from 70% to 100%, a tendency different from that shown by our numerical results (Figure 9(b)). Although the reason for such difference is unclear, the effects of an oral dose of the styrene on the cochlear function should be considered. Unlike the mechanism of noise-induced hair cell loss, the mechanism of styrene-induced hair cell loss must involve a much more complicated pathway; that is, the styrene probably affects not only OHCs but also other parts of the animal.​

In conclusion, the rows matter. It would be interesting if [1] would have looked at states APA, where the loss is in the second layer, so we have an idea of how much "which row" matters.]

Figure 1

Figure 2:

[1]: All Three Rows of Outer Hair Cells are Required for Cochlear Amplification
[2]: Basilar membrane vibration in the basal turn of the sensitive gerbil cochlea
[3]: Relation between out hair cell loss and hearing loss in rats exposed to styrene

 

[FGG]

Let me restate my opinions in a better spirit of what I meant. You're right that I have no idea or reason to believe that the 1st row of OHC would be the one to regrow.

What I really am doing is creating immediate questions about these theories. We need to be precise about what was demonstrated. The study showed that third row OHC poisoning leads to only 5-10 dB shifts. A theory is that the difference between rows is negligible and that high redundancy was what was demonstrated. How do we know it wasn't more? How do we know the attached Figure 1 would reproduce with other orders? From this graph, it appears like losing 1/3 of OHC does little, losing 2/3 does a lot, and after that, it's basically the same thing. But wouldn't the second row also have the most neighbors? It's position also causes it to have different force mechanics on the basilar membrane.

For example, in [1], they looked at a finite element model (which I don't understand) of the cross sections of gerbil cochlea. In particular, the goal of the study was to simulate the impact on basilar membrane displacement as a result of various forces, including outer hair cell amplification, and lack thereof, caused by noise trauma and ototoxicity. This study was based on the experiment in [2] on an actual gerbil.

Anyways, several things from [1] really stood out to me that offered alternative considerations to @Diesel's study on rats [3].

Main point: As was structured in [1], consider that for a given slice of the organ of corti, there are three rows of OHC: OHC-1, OHC-2, and OHC-3. Each one can either be A (active) or P (passive). Hence, one example is AAP to mean active, active, passive (this would be the case in the styrene experiment).

Anyways, in [1], they considered two cases. The first case was various levels of noise trauma. They assumed that noise trauma hits in the order of layer 1, layer 2, then layer 3. So we can have AAA (no trauma), then PAA, then PPA, then PPP (all destroyed).

Interestingly, for ototoxicity, they reversed these assumptions, just like in [3]. Hence, for ototoxicity, the order would go AAA (no ototoxicity), then AAP, then APP, then PPP (all destroyed).

To summarize a bunch of complicated calculations, the attached Figure 2 was generated in [1], measuring changes in BM displacement based on the state of the three rows, respectively. Importantly, note that in both cases (two subfigures in Figure 2), the bar graphs are unsurprisingly monotone decreasing, as obviously more passive rows leads to less BM displacement. But, if we look at case PAA versus case AAP, there is a difference.

Do I think I am proving anything? No. But my point is that the rows matter. Actually, in [1], they underscore my point in a straightforward way. This whole quote is in reference to @Diesel's study [3]:

Another experiment using styrene, which was orally dosed, showed CAP threshold shifts of 8, 34, and 32 dB with 35, 70, and 100% OHC losses from OHC-3 to OHC-1, respectively [21]. In this case, OHC loss from 35% to 70% had greater effects on the cochlear amplification than that of the first 35% or that from 70% to 100%, a tendency different from that shown by our numerical results (Figure 9(b)). Although the reason for such difference is unclear, the effects of an oral dose of the styrene on the cochlear function should be considered. Unlike the mechanism of noise-induced hair cell loss, the mechanism of styrene-induced hair cell loss must involve a much more complicated pathway; that is, the styrene probably affects not only OHCs but also other parts of the animal.​

In conclusion, the rows matter. It would be interesting if [1] would have looked at states APA, where the loss is in the second layer, so we have an idea of how much "which row" matters.]

Figure 1
View attachment 44420

Figure 2:
View attachment 44421

[1]: All Three Rows of Outer Hair Cells are Required for Cochlear Amplification
[2]: Basilar membrane vibration in the basal turn of the sensitive gerbil cochlea
[3]: Relation between out hair cell loss and hearing loss in rats exposed to styrene

Unless I'm going nuts, I think you are misreading the chart. They didn't show PAA versus AAP, they showed PAA vs PPA.

Edit. Nevermind, you were comparing between charts and there is a bit of difference. Wonder how much that would translate to in decibels.

 

[Zugzug]

Unless I'm going nuts, I think you are misreading the chart. They didn't show PAA versus AAP, they showed PAA vs PPA.

For a second, I thought I was going nuts. You're right that in Figure 2 (a), they descend from AAA to PAA, PPA, PPP. But in Figure 2 (b), they descend from AAA to AAP, APP, PPP.

I'm comparing the second bars in Figure 2 (a) and (b).

 

[FGG]

For a second, I thought I was going nuts. You're right that in Figure 2 (a), they descend from AAA to PAA, PPA, PPP. But in Figure 2 (b), they descend from AAA to AAP, APP, PPP.

I'm comparing the second bars in Figure 2 (a) and (b).

With my phone I could at first only see the first graph and I was like... is he high? ...on math?

 

[Zugzug]

With my phone I could at first only see the first graph and I was like... is he high? ...on math?

I wish I was high... God knows we all need to heal our ears and get high for like 5 years straight... Some blunts rolled by @Tweedleman for the whole community.

 

[FGG]

Let me restate my opinions in a better spirit of what I meant. You're right that I have no idea or reason to believe that the 1st row of OHC would be the one to regrow.

What I really am doing is creating immediate questions about these theories. We need to be precise about what was demonstrated. The study showed that third row OHC poisoning leads to only 5-10 dB shifts. A theory is that the difference between rows is negligible and that high redundancy was what was demonstrated. How do we know it wasn't more? How do we know the attached Figure 1 would reproduce with other orders? From this graph, it appears like losing 1/3 of OHC does little, losing 2/3 does a lot, and after that, it's basically the same thing. But wouldn't the second row also have the most neighbors? It's position also causes it to have different force mechanics on the basilar membrane.

For example, in [1], they looked at a finite element model (which I don't understand) of the cross sections of gerbil cochlea. In particular, the goal of the study was to simulate the impact on basilar membrane displacement as a result of various forces, including outer hair cell amplification, and lack thereof, caused by noise trauma and ototoxicity. This study was based on the experiment in [2] on an actual gerbil.

Anyways, several things from [1] really stood out to me that offered alternative considerations to @Diesel's study on rats [3].

Main point: As was structured in [1], consider that for a given slice of the organ of corti, there are three rows of OHC: OHC-1, OHC-2, and OHC-3. Each one can either be A (active) or P (passive). Hence, one example is AAP to mean active, active, passive (this would be the case in the styrene experiment).

Anyways, in [1], they considered two cases. The first case was various levels of noise trauma. They assumed that noise trauma hits in the order of layer 1, layer 2, then layer 3. So we can have AAA (no trauma), then PAA, then PPA, then PPP (all destroyed).

Interestingly, for ototoxicity, they reversed these assumptions, just like in [3]. Hence, for ototoxicity, the order would go AAA (no ototoxicity), then AAP, then APP, then PPP (all destroyed).

To summarize a bunch of complicated calculations, the attached Figure 2 was generated in [1], measuring changes in BM displacement based on the state of the three rows, respectively. Importantly, note that in both cases (two subfigures in Figure 2), the bar graphs are unsurprisingly monotone decreasing, as obviously more passive rows leads to less BM displacement. But, if we look at case PAA versus case AAP, there is a difference.

Do I think I am proving anything? No. But my point is that the rows matter. Actually, in [1], they underscore my point in a straightforward way. This whole quote is in reference to @Diesel's study [3]:

Another experiment using styrene, which was orally dosed, showed CAP threshold shifts of 8, 34, and 32 dB with 35, 70, and 100% OHC losses from OHC-3 to OHC-1, respectively [21]. In this case, OHC loss from 35% to 70% had greater effects on the cochlear amplification than that of the first 35% or that from 70% to 100%, a tendency different from that shown by our numerical results (Figure 9(b)). Although the reason for such difference is unclear, the effects of an oral dose of the styrene on the cochlear function should be considered. Unlike the mechanism of noise-induced hair cell loss, the mechanism of styrene-induced hair cell loss must involve a much more complicated pathway; that is, the styrene probably affects not only OHCs but also other parts of the animal.​

In conclusion, the rows matter. It would be interesting if [1] would have looked at states APA, where the loss is in the second layer, so we have an idea of how much "which row" matters.]

Figure 1
View attachment 44420

Figure 2:
View attachment 44421

[1]: All Three Rows of Outer Hair Cells are Required for Cochlear Amplification
[2]: Basilar membrane vibration in the basal turn of the sensitive gerbil cochlea
[3]: Relation between out hair cell loss and hearing loss in rats exposed to styrene

It seems like they are saying that for a given amount of at least mild hair cell loss, you would see less of a basilar membrane movement reduction for noise induced losses (which they say tend to happen with the 1st row first but I would argue based on the study HootOwl posted that would only be necessarily true for the band of noise they used) than ototoxicity. It probably matters which ototoxin you use as well.

As you pointed out, how that translates into action potential wasn't measured for each position of loss.

But also in either case, the second row seems to matter the most. I.e. whether you lose 1st row or 3rd row first, the 2nd row causes the most deterioration from there.

What's really interesting about these studies is it seems even if you lose all your OHCs, you still max out around 60 dB of loss, so if you have more you have lost IHCs for sure.

And that means the individual audiogram data for the severe group will be especially useful.

 

[FGG]

I wish I was high... God knows we all need to heal our ears and get high for like 5 years straight... Some blunts rolled by @Tweedleman for the whole community.

I would (and I mean this literally) trade the entire rest of my life and die happy for just one day of getting high and listening to music with normal ears.

 

[Zugzug]

It seems like they are saying that for a given amount of at least mild hair cell loss, you would see less of a basilar membrane movement reduction for noise induced losses (which they say tend to happen with the 1st row first but I would argue based on the study HootOwl posted that would only be necessarily true for the band of noise they used) than ototoxicity. It probably matters which ototoxin you use as well.

As you pointed out, how that translates into action potential wasn't measured for each position of loss.

But also in either case, the second row seems to matter the most. I.e. whether you lose 1st row or 3rd row first, the 2nd row causes the most deterioration from there.

What's really interesting about these studies is it seems even if you lose all your OHCs, you still max out around 60 dB of loss, so if you have more you have lost IHCs for sure.

And that means the individual audiogram data for the severe group will be especially useful.

Yeah, I guess I showed the opposite of @Diesel's post. The study I posted predicts that in both PAA (noise trauma) and AAP (ototoxicity) situations, there's a big drop off from AAA. Could it be a difference between rats and gerbils?

I would like to see the second row isolated. The problem is they only considered two cases: increasing damage from 1st to 3rd or 3rd to 1st. It's not surprising that the more rows included, the more damage. Both studies concluded similarly that once OHC is depleted all-together, it's not the end of the story. I found that to be really interesting as well, as it's really saying there are volume levels where IHCs don't need amplification at all.

 

[Zugzug]

Literally, this is me. He is Walter White.

 

[FGG]

Yeah, I guess I showed the opposite of @Diesel's post. The study I posted predicts that in both PAA (noise trauma) and AAP (ototoxicity) situations, there's a big drop off from AAA. Could it be a difference between rats and gerbils?

I would like to see the second row isolated. The problem is they only considered two cases: increasing damage from 1st to 3rd or 3rd to 1st. It's not surprising that the more rows included, the more damage. Both studies concluded similarly that once OHC is depleted all-together, it's not the end of the story. I found that to be really interesting as well, as it's really saying there are volume levels where IHCs don't need amplification at all.

But we actually can't generalize about the effects of noise exposure (e.g., The study HootOwl posted). We can only say that the particular noise used in that study produced those results. Same with Ototoxins.

@HootOwl and I actually talked about about this before, they thought Liberman was nuts for saying that you could even destroy something like 70% of synapses without *any* hair cell damage with a very specific noise exposure but he did just that.

 

[Zugzug]

@HootOwl and I actually talked about about this before, they thought Liberman was nuts for saying that you could even destroy something like 70% of synapses without *any* hair cell damage with a very specific noise exposure but he did just that.

Liberman? Who's that? Are we in church?

 

[FGG]

Yeah, I guess I showed the opposite of @Diesel's post. The study I posted predicts that in both PAA (noise trauma) and AAP (ototoxicity) situations, there's a big drop off from AAA. Could it be a difference between rats and gerbils?

I would like to see the second row isolated. The problem is they only considered two cases: increasing damage from 1st to 3rd or 3rd to 1st. It's not surprising that the more rows included, the more damage. Both studies concluded similarly that once OHC is depleted all-together, it's not the end of the story. I found that to be really interesting as well, as it's really saying there are volume levels where IHCs don't need amplification at all.

It is actually possible that gerbils are unique:

Acoustic distortion from rodent ears: A comparison of responses from rats, guinea pigs and gerbils

I usually don't see them used much outside of some age-related studies. But lab rats are also more common anyway.

 

[FGG]

Liberman? Who's that? Are we in church?

He's the researcher that discovered cochlear synaptopathy.

 

[serendipity1996]

But we actually can't generalize about the effects of noise exposure (e.g., The study HootOwl posted). We can only say that the particular noise used in that study produced those results. Same with Ototoxins.

@HootOwl and I actually talked about about this before, they thought Liberman was nuts for saying that you could even destroy something like 70% of synapses without *any* hair cell damage with a very specific noise exposure but he did just that.

There's a really great talk Liberman gave back in 2016 - a deep-dive on cochlear synaptopathy where he states that you can even lose up to 90% of your nerve fibers - from 4:30 onwards: "but you can lose possibly up to 90% of the fibers in your auditory nerve so long as it's done fairly evenly distributed across the cochlear spiral and there'll be absolutely no effect on the audiogram."



This is actually a super informative talk though - captions available too. Need to rewatch it lol.

 

[Zugzug]

He's the researcher that discovered cochlear synaptopathy.

Oh, I know. I was making a joke that there are so few legit researchers that we should deify all of them.

 

[FGG]

Oh, I know. I was making a joke that there are so few legit researchers that we should deify all of them.

Lol. Some of my family is the weird kind of Southern Baptist so my first thought was maybe you meant calling up weird, meaningless names from speaking in tongues.

 

[Zugzug]

Lol. Some of my family is the weird kind of Southern Baptist so my first thought was maybe you meant calling up weird, meaningless names from speaking in tongues.

Actually, to be honest, I don't even know how to pronounce his name. I often say Lee-berman in my head, but it's probably Lie-berman. This is the case with many things I have learned. Why? Because I have never actually heard them, just read them. I don't really know how to say Nicotinamide Riboside. I YouTube searched the pronunciation before a doctor appointment one time. I probably don't know how to pronounce half of the scientific terms I've learned over the past two years.

Also, very funny, I didn't know Fauci was pronounced "Fouchy," and didn't learn this until about a year into the pandemic, despite knowing full well who he was. One time at dinner, I name dropped Fauci and my wife corrected me and explained that the vaccine was called the "Fauci ouchy" because of his name.

Anyways, this has absolutely nothing to do with the joke I was intending. If I don't even know who Charles Liberman is, the dude's life work is truly a waste lol.

 

[Diesel]

Ok here's my theory + diagrams...

Let's set a few parameters first:

The makeup of the IHC + OHC in the cochlea:
A single human cochlea generally has about 3500 ROWS consisting of 1 IHC + 3 OHC. This enables most people to hear from 20 Hz - 20 kHz. So, back of the napkin math tells us that each row is responsible for roughly 5.7 Hz sensitivity. Since the biology cochlea isn't based on the Hz measurement, it stands to reason that the metric itself doesn't matter all that much in figuring out what each row can actually detect. Especially since the human cochlea is able to distinguish between two frequencies 1 Hz apart.

What I have come to understand is that each row has a lot of overlap in terms of sensitivity to frequencies. It appears that there is considerably more overlap in sound frequency sensitivity amongst IHC, but not as much in terms of decibels; they provide a flat signal to the brain. The OHC do not have the same level of overlap in frequencies, and are much more fine tuned to specific frequencies; due to their mechanical nature, they're able to tune based on the power (decibels) of sound received by the cochlea. When a sound is faint, they can turn a signal "up", when it is loud, turn it down. Etc.

Diesel's diagrams:

For the sake of example, let's assume that each row of hair cells translates to roughly 5 Hz of frequency sensitivity. In the first example, we see a sample of healthy cochlea, centered on the 4 kHz location +/1 20 Hz.

The far left figure indicates the frequency that the IHC can still "detect", and since they are green, the IHC row is fully sensitive to the entire sample. The IHC row indicates that the cell is present. Green = present. Red = dead/destroyed. The next three OHC rows indicate the adjacent OHC. Again, all are green and present. The far right row indicates the sensitivity of the OHC SET (all three) at the specified frequency.

Ok, let's look at what happens when damage occurs above and below the 4000 Hz row. Leaving the 4000 Hz cells alive and healthy:

IHC: The 4000 Hz IHC is still able to detect adjacent frequencies above and below 4000 Hz to an extent. At 3985 Hz + 4015 Hz, sensitivity is partial.

OHC: The OHC cannot detect beyond its missing neighbor.

In this example, the audiogram would look NORMAL at 4000 Hz. Word score may be ok as well.

Let's look at another example:

Here, the 4000 Hz row stays alive, as does the 4020 Hz row.

IHC: Due to the larger range of sensitivity of the IHC, they are able to continue to detect sound well from 3990 Hz - 4020 Hz and beyond. YET, there are IHC missing from 3 frequencies in the middle.

OHC: Again, lacking range in sensitivity, an audiogram test at 4005 Hz - 4015 Hz may reveal a deficit.

So, let's take the same example and pick off an OHC at 4000Hz:

IHC: Coverage still looks good. Word Score should be retained.

OHC: May be an issue apparent on the audiogram at 4000 Hz.

Let's mix it up. What if only Rows at 3980 Hz and 4020 Hz survive?

IHC: Severe deficit at 4 kHz. But, overall coverage in this sample is still not terrible.

OHC: Severe deficit at 4 kHz. Overall deficit from 3985 Hz - 4015 Hz. Would definitely appear on audiogram.

Ok, one last sample re: damage to bring it home.

Keep the outer rows normal. Damage the 4 kHz OHC only.

IHC: Almost total coverage. WR score should remain excellent.

OHC: Obvious deficits. Would be visible on audiogram. I believe this would show a mild loss if the research correlates from the "Diesel Rat" study.

 

[just1morething]

What if Frequency Therapeutics' next trial flops? Will FREQ stock drop below $5? I hope a single dose trial has good results if that is their plan, but you can't blame people that are skeptical at this point. An echo chamber of positive people regarding FX-322 is not always good, especially those that are investors.

 

[Guywithapug]

There's a really great talk Liberman gave back in 2016 - a deep-dive on cochlear synaptopathy where he states that you can even lose up to 90% of your nerve fibers - from 4:30 onwards: "but you can lose possibly up to 90% of the fibers in your auditory nerve so long as it's done fairly evenly distributed across the cochlear spiral and there'll be absolutely no effect on the audiogram."

This is actually a super informative talk though - captions available too. Need to rewatch it lol.

Nice find, I will definitely watch it soon.

Regarding the auditory nerve, does anyone here know if strands of the nerve are frequency specific when electrical impulses are en route to the brain?

Or is it more like an electric wire where as long as there is continuity, a signal will get through?

Pardon my ignorance.

 

[Tezcatlipoca]

What if Frequency Therapeutics' next trial flops? Will FREQ stock drop below $5? I hope a single dose trial has good results if that is their plan, but you can't blame people that are skeptical at this point. An echo chamber of positive people regarding FX-322 is not always good, especially those that are investors.

This is not an investment forum.

 

[Lucifer]

What if Frequency Therapeutics' next trial flops? Will FREQ stock drop below $5? I hope a single dose trial has good results if that is their plan, but you can't blame people that are skeptical at this point. An echo chamber of positive people regarding FX-322 is not always good, especially those that are investors.

I think age-related hearing loss trial should have no problem passing but I'm a bit worried about the severe hearing loss trial. I still believe FX-322 will do something for severe hearing loss sufferers e.g. the ability to hear high frequencies a lot better.

 

[FGG]

Ok here's my theory + diagrams...

Let's set a few parameters first:

The makeup of the IHC + OHC in the cochlea:
A single human cochlea generally has about 3500 ROWS consisting of 1 IHC + 3 OHC. This enables most people to hear from 20 Hz - 20 kHz. So, back of the napkin math tells us that each row is responsible for roughly 5.7 Hz sensitivity. Since the biology cochlea isn't based on the Hz measurement, it stands to reason that the metric itself doesn't matter all that much in figuring out what each row can actually detect. Especially since the human cochlea is able to distinguish between two frequencies 1 Hz apart.

What I have come to understand is that each row has a lot of overlap in terms of sensitivity to frequencies. It appears that there is considerably more overlap in sound frequency sensitivity amongst IHC, but not as much in terms of decibels; they provide a flat signal to the brain. The OHC do not have the same level of overlap in frequencies, and are much more fine tuned to specific frequencies; due to their mechanical nature, they're able to tune based on the power (decibels) of sound received by the cochlea. When a sound is faint, they can turn a signal "up", when it is loud, turn it down. Etc.

Diesel's diagrams:

For the sake of example, let's assume that each row of hair cells translates to roughly 5 Hz of frequency sensitivity. In the first example, we see a sample of healthy cochlea, centered on the 4 kHz location +/1 20 Hz.

The far left figure indicates the frequency that the IHC can still "detect", and since they are green, the IHC row is fully sensitive to the entire sample. The IHC row indicates that the cell is present. Green = present. Red = dead/destroyed. The next three OHC rows indicate the adjacent OHC. Again, all are green and present. The far right row indicates the sensitivity of the OHC SET (all three) at the specified frequency.

View attachment 44429

Ok, let's look at what happens when damage occurs above and below the 4000 Hz row. Leaving the 4000 Hz cells alive and healthy:

IHC: The 4000 Hz IHC is still able to detect adjacent frequencies above and below 4000 Hz to an extent. At 3985 Hz + 4015 Hz, sensitivity is partial.

OHC: The OHC cannot detect beyond its missing neighbor.

In this example, the audiogram would look NORMAL at 4000 Hz. Word score may be ok as well.

View attachment 44430

Let's look at another example:

Here, the 4000 Hz row stays alive, as does the 4020 Hz row.

IHC: Due to the larger range of sensitivity of the IHC, they are able to continue to detect sound well from 3990 Hz - 4020 Hz and beyond. YET, there are IHC missing from 3 frequencies in the middle.

OHC: Again, lacking range in sensitivity, an audiogram test at 4005 Hz - 4015 Hz may reveal a deficit.

View attachment 44434

So, let's take the same example and pick off an OHC at 4000Hz:

IHC: Coverage still looks good. Word Score should be retained.

OHC: May be an issue apparent on the audiogram at 4000 Hz.

View attachment 44435

Let's mix it up. What if only Rows at 3980 Hz and 4020 Hz survive?

IHC: Severe deficit at 4 kHz. But, overall coverage in this sample is still not terrible.

OHC: Severe deficit at 4 kHz. Overall deficit from 3985 Hz - 4015 Hz. Would definitely appear on audiogram.

View attachment 44436

Ok, one last sample re: damage to bring it home.

Keep the outer rows normal. Damage the 4 kHz OHC only.

IHC: Almost total coverage. WR score should remain excellent.

OHC: Obvious deficits. Would be visible on audiogram. I believe this would show a mild loss if the research correlates from the "Diesel Rat" study.

View attachment 44437

I get the point you are making but there are probably not many disease processes that would cause a lake of severe with an island of completely normal but with more moderate disease, sure, feasible. Still graphically illustrates the limits of testing really well!