Pain Hyperacusis in Relation to Acoustic Shock & Synapse Disconnection

Thank you.

So did you see the middle ear video Hyperacusis Research posted? I haven’t been able to find a summary of it.

 

No, I've only seen Megan Wood's talk as the captions weren't very good for the middle-ear talk. Going to have to revisit it!

 

I didn't know that, that's really interesting - I hope they do more research into this!

Yeah, I think the middle ear muscles definitely play a role - my right ear sort of thumps and spasms occasionally now. It's not painful or anything but quite annoying.

 

Do you have symptoms like this? This is from Caring Medical.

TMJ surgery and appliances do help people. But these are not the patients we see in our clinic. We see the people TMJ surgery and appliances did not help. These are people, perhaps like yourself, whose TMJ has turned into a problem of tinnitus, headaches, neck pain, difficulty swallowing, and dizziness.

https://www.caringmedical.com/prolotherapy-news/tmj-tinnitus/​

 

No, I don't have TMJ - no dizziness, neck pain, headaches or swallowing problems.

 

Could you try an auriculotemporal nerve block? I read that nerve controls the inner ear muscles.

 

In a Facebook group that I follow, two people recently reported improvement in pain hyperacusis with calcium channel blockers.

One person used Sibelium and said their severe hyperacusis reduced by 90% while on the medication. This medication is not available in the US.

A second person, a doctor with pain hyperacusis, said that he takes Diltiazem, another calcium channel blocker, and it’s helped with his ear pain.

I’d love to know if anyone else has tried similar medications.

 

NO WAY! I had previously speculated calcium channel blockers would work months ago after reading that zebrafish study but it seemed to fall on deaf ears. I'm going to link it again. Keep in mind my post links to another post on this, also linked below.

Kava Kava for Tinnitus — Post Your Experience!

Pain Hyperacusis in Relation to Acoustic Shock & Synapse Disconnection

Edit: copy-pasting original post below:

"I wonder what the consequences of having smaller/larger ribbon sizes are? Would I be right in guessing that a larger ribbon size would mean there's a greater chance of synapsing the OHCs to the type II afferents?

I've been giving more and more thought to this inverse relationship Fuchs alluded to between the type 1 and 2 afferents post noise exposure. I want to bring to everyone's attention this passage from the zebrafish study:

"decreasing voltage-gated Ca2+ influx through CaV1.3 channels during development led to the formation of ... larger ribbons. Furthermore, in mouse knockouts of CaV1.3, auditory outer hair cells have reduced afferent innervation and synapse number."

For those who don't know, a knock-out mouse is a mouse that's been genetically engineered to not have a particular gene by disrupting it with a piece of artificial DNA. So these mice were genetically engineered to not have the voltage-dependent calcium channel and the result was less afferent innervation and synapse numbers, suggesting that the calcium channels play an important role in regulating the synapse numbers. If we know from the recently released Fuchs study that synapse numbers of OHCs increase after noise exposure, this would suggest that noise exposure disrupts the function of the calcium channel in the complete opposite manner than that seen in the knock out mouse. I also recall from Liberman's work that IHCs in the high frequency region of the mouse cochlea have enlarged ribbons immediately after noise, followed by synapse loss.

So where I am going with this? In short, I am inferring that the dysfunctional Cav1.3 calcium channels may be the smoking gun here with regards to what's causing our hyperacusis. I've had a quick look online to see what other diseases and conditions are caused by dysfunctional Cav1.3 calcium channels and the biggest one seems to be Parkinson's, which is sometimes treated with calcium channel blockers. Interestingly, the zebrafish study has something to say here:

"Recent work in mice has investigated the role of the MCU in noise-related hearing loss. This work demonstrated that pharmacological block or a loss of function mutation in MCU protected against synapse loss in auditory inner hair cells after noise exposure".

I just wonder: could a calcium channel blocker, such as a Parkinson's-prescribed drug, help us with our symptoms?

Would love to get some feedback on this and I again encourage everyone to read this zebrafish study!"

@FGG, @Diesel, @Zugzug, @serendipity1996, @100Hz, please all read.

 

LOL, yep! I thought you might find that I interesting

Unfortunately, the person who was taking Sibelium was told to stop after 6 months because they were told it INCREASED the chances of Parkinson’s if taken for extended periods. I’m not sure how true that is or not. They said that their symptoms have started coming back now that they are off the medication.

The man taking Diltiazem had this to say, “Calcium channel blockers are also effective at migraine prophylaxis. People with migraine can develop hyperacusis, ear pain, and endolymphatic hydrops, with or without classic migraine headaches. Diltiazem (a calcium channel blocker) has helped my symptoms, notably the ear pain!” He also said it was his neurotologist who suggested it.

 

There are some UK guidelines that recommend against its use if you have 1) depression or previous episodes of severe depression, 2) a family history of Parkinson's disease, and 3) liver damage.

 

This seems to be another reason Magnesium is so helpful. Magnesium's effects include calcium blockade.

Has anyone else tried injectable IM Magnesium btw? It definitely helps but I ran out and don't have access to more so I'm using oral instead (helps but not nearly as well). Sometimes naturopath doctors do this for patients for literally any kind of pain but especially fibromyalgia.

 

Not injectable but I do drink liquid magnesium a few times a week. Back in the beginning of hyperacusis I was drinking it every day. It took my symptoms from catastrophic to severe.

 

Guess I won't be trying it then lol.

 

Try to find someone to give you an IM Magnesium injection and see how you do...

 

Do you think the type matters, like L-Threonate or Glycinate?

I can’t take anymore than 100mg of Magnesium without feeling faint, but I suppose a little is better than none...

 

I don't have much luck personally with anything but oral (not topical) Magnesium Chloride but it probably varies from person to person.

 

This is maybe a golden find @Aaron91. It helps me join 2 maybe major dots together in my own theory. I've been working on something as you know recently and spent a long time focusing purely on the mechanism of the tip link MET channels. In normal hair cell stereocilia there's a consistent stable regulation of K+ to the MET channels depending on whether the stereocilia are hyperpolarized (closed) ~-60mV, resting (semi-closed I believe) ~-40mV, or depolarized (fully open - which I understand triggers the influx of Ca2+) ~-20mV. When focusing on damaged hair cells however I wondered how different levels and type of damage may interfere with the regulation of K+ into the the MET channels. i.e. if tip links are permanently broken in extreme cases (they are capable of repairing themselves under certain / normal circumstances), do the MET channels remain permanently closed or severely dysfunctional? And also the reverse scenario where maybe a bent stereocilia with an intact tip link may force a MET channel permanently open - this is all highly speculative btw.

I need to think about this because I'm still a bit vague on the details but in a way it doesn't matter because if an enlarged ribbon is due to reduced Ca2+ influx either because the MET channels are not opening upon depolarization (or for some perverse reason due to them permanently open during hyperpolarization and resting), then that indicates OHC damage, and if OHCs are damaged then they are more likely to respond to FX-322 PCA. A huge worry I have had (probably my biggest) is that extra ribbon OHCs are not damaged, or at least are not damaged enough to respond to FX-322 PCA, and would require some type of targeted ablation prior to FX-322. A study concept I'd hate to speculate is even happening yet.

@Aaron91 please can you link the zebrafish study again, the particular one you always talk about. Thx.

 

I think my pain is most like yours compared to anyone else's in this thread, so I did want to ask, has your tinnitus changed since getting noxacusis?

My (moderate) tinnitus does not fluctuate *at all* through any of this even when I can feel my TM flutter and I'm wondering if I am in the minority here. My actual ear pain is much more minor than my face pain which has ramped up considerably again after tapering off Pred so I think this kind of pain:

1) has a large classically inflammatory component.

2) seems heavily weighted towards the middle ear and secondary trigeminal stimulation.

How is your pain now?

 

My tinnitus was also very mild, I sometimes don’t hear it at all and it’s only my right ear.

It’s still the same, gets a little better and a little worse depending on the day.

 

How long have you had it again? No trending upward yet?

 

It got worse for a few months and then stayed stagnant for the most part. I’m still trying to figure out what to do about it. I’m thinking about asking a trigeminal nerve block or something. I figure that if they can just get pain out of my face, I won’t even care about the sound intolerance.

 

If facial pain is your biggest issue, have you tried or considered Tegretol or Trileptal? I believe those are normally the most effective medications for that type of pain. Only issue with those is that they lessen the effect of benzos which could be a problem if you use them regularly.

I did a trial run with Trileptal recently and it did seem to help some with my ear pain in the short time that I took it. I would want to taper off of my benzo before taking it long term, though. Taking both at the same time seemed to spike my tinnitus.

 

I haven’t tried Tegretol yet but if Gabapentin doesn’t work, I will. But I really want to see if any of the facial nerve blockers could help.

 

Totally understand. All of these medications have side effects that can sometimes be worse than what they are meant to treat. If a nerve block takes care of it then you can avoid the side effects of the medication

 

Very interesting @100Hz, I need to read more. In the meantime, here's the zebrafish study:

Synaptic mitochondria regulate hair-cell synapse size and function

And here were my initial comments prior to the ones I posted above:

"Great question @serendipity1996 and I've been having exactly the same thoughts since you shared that study. I have since read this recent study by Wong et al., which looks at synaptic ribbon regulation in zebrafish. It has some interesting parallels with the Paul Fuchs study and raises some interesting questions. Here are just a few quotes below from that study and my thoughts on them:

"in the mammalian auditory system, ribbon size is correlated with differences in afferent activity".

"Compared to smaller ribbons, larger ribbons within inner hair cells are innervated by afferent fibers with higher thresholds of activation and lower rates of spontaneous activity"

"Functionally, compared to controls, hair cells with enlarged ribbons were associated with afferent neurons with lower spontaneous activity"​

So my first obvious takeaway here is that there is relationship between ribbon size and afferent activity. My second takeaway is that the larger the ribbon size, the more likely there is to be an innervation between the inner hair cell and the afferent type I fibres, although I can't be sure on this and would like to have this confirmed. My third takeaway, assuming my second takeaway is correct, is that once you have that innervation because of the enlarged ribbons, there is less spontaneous activity. Now, I really emphasise the word spontaneous, because as we have all read before, the argument goes that it is spontaneous "activation" of neurons in the type II afferents that causes hyperacusis. This would confirm my thoughts, and I believe what @serendipity1996 was also trying to get at: that there is an inverse relationship in the number and activity between the type I and type II afferent fibres respectively.

So this is all really enlightening and I'm sure some of you are now wondering what can we do to affect ribbon sizes. This is where the news isn't so great:

"After a 1 hr treatment with 100 µM NAD+, we found that the ribbons in developing hair cells were significantly larger compared to controls. In contrast, after a 1 hr treatment with 5 mM NADH, ribbons were significantly smaller compared to controls. Neither exogenous NAD+ nor NADH were able to alter ribbon size in mature hair cells. These concentrations of NAD+ and NADH altered neither the number of synapses per hair cell nor postsynapse size in developing or mature hair cells. These results suggest that in developing hair cells, NAD+ promotes while NADH inhibits Ribeye-Ribeye interactions or Ribeye localization to the ribbon. Overall these results support the idea that during development, the levels of NAD+ and NADH can directly regulate ribbon size in vivo"​

The long and short of it here is that NAD+/NADH do seem to affect ribbon sizes, but not when they come from exogenous sources. It goes without saying this absolutely sucks, because it means not even an NAD+ or NADH supplement could help us, although it is very unclear to me which of the two we would need because they seem to have the opposite effect. A larger ribbon size induced from NAD+ would help with IHC innervation to the type I afferents, but does this mean it would also help with innervating OHCs to the type II afferents, which presumably is something we don't want? Conversely, a smaller ribbon size would reduce the chance of OHC innervation to the type II afferents, but then also do the same for IHCs and type I afferents. This sucks because the relationship here, as I said above, is an inverse one. If one goes up, the other must come down.

Finally, I feel that these two studies have perhaps answered a question I've had for a long time: why are there some children with seemingly perfectly healthy cochleas that have not been exposed to noise damage but have hyperacusis?

Well, here's a quote from the Paul Fuchs study:

"The number of ribbons in OHCs declines soon after birth, with that change essentially complete in the first postnatal week"​

And here's a quote from the 2019 Wong study:

"Interestingly, in mice differences in ribbon size can be distinguished just after the onset of hearing. This timing suggests that similar to our data, activity during development may help determine ribbon size"​

And here's one more quote from a study quoted by @100Hz.

"Of interest in this context is the previous report that sensitivity to ATP is reduced in type II afferents after the onset of hearing"​

This for me says a lot. The first quote says that OHCs decline soon after birth and the last one says that sensitivity to ATP is reduced after the onset of hearing (i.e. birth), implying that there is a direct correlation between upregulation of pain receptors due to excess ATP and the number of ribbons. I would therefore guess that kids who are born with hyperacusis don't 'shed' their excess OHC ribbons, leaving the type II afferents prone to sensitivity. The question then is: how we can shed our excess OHC ribbons, which we seem to have to gained following noise exposure?"

 

Exactly @Aaron91. If I'm right in thinking that ribbons, along with extra, enlarged ribbons die along with an OHC when an OHC dies then it would be good to know that these lingering dodgy extra ribbon OHCs are damaged and can have PCA activated by FX-322. If they are skipped by FX-322 because they are seen as healthy then that's where I get stuck thinking about what next, and end up at Xen & RL-81?

But the calcium channel stuff you posted above really helps me to believe that there is damaged involved now.

Thanks for the study. I'll go through it properly.

 

I'm focusing lately on how OAE tests could be useful to measure improvements in the inner ear that aren't detectable on an audiogram. The theory applies to 2 sets of criteria as below. (Originally roughly outlined on FX-322 thread but I've come to realize that this also applies here to one of the sets of criteria so I've now put the theory together as thoroughly as I can).

Basically I understand that an OAE test is picking up damage that might not show on an audiogram, and that FX-322 is possibly fixing something that also does not reflect on an audiogram and so I'm trying to imagine how an OAE test may help to pick up on these seemingly unquantifiable improvements.

The first set of criteria is:

1. THE CURRENT FX-322 TRIALS CASE (substandard audiogram due to typical hearing loss that doesn't reflect significantly an improvement after trial, but does in some cases show improvement in other ways such as WR score).

• Typical hearing loss (does show on an audiogram at baseline).
• If OAE tests were involved they may pick up an extra, more granular layer of damage where an audiogram may not be able to and help to back up an improvement in WR score when taken again post trial.
• The possibility that FX-322 could be the first drug that is fixing something that might not show up as an improvement on an audiogram but might be detectable with other tests (WR, SIN, and importantly an OAE test). In other words, I don't think it could have ever been proven exactly what an OAE test was measuring as FX-322 is the first proposed regeneration drug. An OAE test may be as useful in determining what FX-322 fixes as FX-322 is in determining what an OAE test is capable of measuring.

I won't continue with the above criteria because it is typically measurable hearing loss / FX-322 trials related.


The second set of criteria that does fit into this thread however is:

2. THE CASES OF NON HEARING LOSS RELATED HEARING PROBLEMS (the case of a generally good audiogram, but where an obvious, yet 'cause unknown', hearing problem of some other nature does exist).

• Tinnitus / hyperacusis (maybe noxacusis) / hidden hearing loss (and therefore may show a healthy audiogram).
• OAE tests do pick up apparent damage where the audiogram may not be able to.
• The possibility that FX-322 could be the first drug that is fixing something that might not show up as an improvement on an audiogram but might be detectable with other tests (WR, SIN, and importantly an OAE test). In other words, I don't think it could have ever been proven exactly what an OAE test was measuring as FX-322 is the first proposed regeneration drug. An OAE test may be as useful in determining what FX-322 fixes as FX-322 is in determining what an OAE test is capable of measuring.

Note - highly likely there is some combination of the 2 above scenarios.
Note - as far as I'm aware, OAE tests are neither subject to conscious nor unconscious bias.

1. Healthy hearing (healthy IHCs, OHCs, afferents, synapses): Self explanatory, good OAE test, good audiogram, good WR score.



2. Damaged OHCs. What state everything else is in is unknown. Apparently OAE tests are testing for OHC damage and this is how I interpret what I am lead to believe about them. In the case below it is picking up OHC damage before it shows on an audiogram (common with OAE tests apparently). WR score in this case I'm not sure about but I imagine would depend on any IHC damage.



3. The above may well be true especially if there is also a substandard audiogram, but what if in certain circumstances (tinnitus, poor WR / WIN, maybe hyperacusis / noxacusis for example) where audiogram is good but OAE tests and WR scores are substandard, there is actually nothing wrong with OHCs (or minimal damage to OHCs) and the reason for the lack of OAE emissions is that OHCs are being influenced by damage from another source (IHCs, afferents, synapses etc.).



4. If a baseline test was taken that could show substandard OAE emissions, and substandard WR score alongside a good audiogram, and then treatment was administered, IF the treatment was targeting IHCs either first before OHCs, or simply bypassing OHCs altogether (maybe not damaged enough for PCA?), could this resultant regeneration of IHCs and IHC synapses be leading to the final outcome of an improved WR score that could now be backed up with an improved OAE test?



5. Post trial shows regenerated IHCs and IHC synapses. Whether or not the OHCs are damaged, minimally damaged, or very damaged, they do not appear to show much improvement on an audiogram after treatment for some reason. If improved WR scores could be backed up with an improved OAE test, which again I don't believe is subject to bias, could this finally not just show that the treatment was working for something other than OHCs but also indicate that an OAE test was picking up damage from somewhere other than OHCs in the first place?



I'm not new to this kind of trouble shooting. I was a network analyst for many years and routinely had to diagnose both why something was broken and sometimes why a particular fix was fixing the the problem (often more difficult). It wasn't uncommon to use every method of diagnostics and monitoring available in order to stand a chance of highlighting and pinpointing the specific X factor and often where many monitors would fail, just one would highlight the exact thing we were looking for. I know it's not that simple with hearing regeneration but for that reason alone I can't understand why as many tests as possible were not run at baseline plus at post trial for the FX-322 trials. I can't see anything to lose by doing this (at least trying it once).

For example I would run the following tests at baseline and post trial:

• WR (currently the benchmark and all we have to hold onto in terms of improvement. Not much since the Phase 2a read out, but a start).
• OAE (could back up a WR score improvement).
• WIN (not sure about this test but I don't see what harm it could do especially if it's more an IHC related test).
• Audiogram (although apparently not very useful, I don't see what harm it would do to also run it as even a very very small trend in improvement may also correspond to larger more obvious trends of improvement in the above tests).

Running these extra tests could provide the following benefits:

• An improvement in OAE results could help to corroborate a trend of non biased participants who also improve in WR score.
• A trend of bias could be observed among placebo participants who improve WR but not OAE (along with comparison to history for additional measure).
• It could also be a measure for the theory of why some participants do VERY WELL.
• For suspected bias drug treated participants who do not improve WR but do improve OAE, it could indicate trying to throw the trial (and also could be compared with history for additional measure).

Anyway @Aaron91, @Diesel, @serendipity1996, @FGG, @Zugzug calling on your big gun analysis for this theory.

 

What is an OAE test and is it loud?

 

Sorry, it took so long to respond. I think OAEs make sense but depending on how bad your hyperacusis is, it could possibly exacerbate it. I actually had OAEs done because my hearing seemed a lot worse than my audiogram. It actually came back normal (My OHC damage is substantial but it's all below 100 Hz and above 10000 Hz)--which shows the limits of the test beyond a certain range.

And you are right. They should have used it for the FX-322 trial, even if they would still have to stick to audiogram measurements for the EHF. You could then objectively determine if a 10 dB improvement was an actual improvement or test/retest variation.

 

Started Ambroxol today. I was going to wait and see how I did on antivirals first but had a bad night last night. So I knocked myself out with Benadryl, woke up better but still sore and started Ambroxol 30mg TID.

After 3 doses, I think there is already some improvement. Interestingly enough, my TTTS eardrum dull ache-not quite pain is exactly the same but my facial pain seems better.

I'm still in the early, heavily fluctuating stage so I can't be sure it's the drug.

But I did come across this today, which suggests the drug may be good directly for middle ear inflammation:

https://www.actamedicamediterranea....patients-with-secretory-otitis-media/document

I know I am confounding variables here (in addition to the antivirals, I also started fasting) and if I get better, I might not know why, but that's what a really bad night will do I guess.