Questions Regarding AM-101 and TRT

Hey guys, I have been doing some research trying to wrap my head around all of this tinnitus stuff, and I was hoping to get some input. I’m going to explain the way I interpret the current tinnitus theory in terms of both AM-101 and TRT, and then I'll ask a few questions about my interpretation. Also, I wan't exactly sure which category to put this in, but because this post is related to the details of AM-101 (not yet an available treatment) I decided to put it in "Research News". Please feel free to change this if it would be better someplace else.

Tinnitus Theory

If my understanding is correct, when damage to the sensory inner hair cells (IHCs) occurs, the central auditory system (CAS) increases the presence of the neurotransmitter glutamate at the synapses linking the IHCs and the dendrites of the afferent primary auditory neurons (PANs) creating a "glutamate storm". This increase in glutamate is triggered by the CAS through efferent projections from the brain to the dendrites of the IHCs. The CAS excites the IHCs when there is a lack of proper signaling, which is meant to illicit a stronger response. At this point, excitotoxicity (high levels of calcium ions are allowed to enter the cell) occurs when the excess glutamate begins to continuously trigger the normally unused NMDA receptors. This trauma causes the IHCs to fire a signal along their associated PANs and also damages / destroys the IHCs.

The idea behind AM-101 (eskatamine, a non-competative NDMA receptor antagonist) is that the IHC’s NMDA receptors will be blocked from the glutamate storm, giving the cell relief while it can begin to repair itself. Eventually though, the drug will leave the body, and the NMDA receptors will be open again. So, I am assuming it is normal for the glutamate storm to stop once the CAS either adjusts to the loss of signal or once again receives a correct signal.

For someone who does not take AM-101, the NMDA receptors of the IHCs will be overloaded with glutamate, and IHCs will cause the associated PANs to fire due to the trauma. I believe that the glutamate storm will eventually end once the CAS adjusts, but leaving the IHC damaged or dead.

These are the cases I can come up with in terms of what can happen during the period of time in which the glutamate is impairing an IHC:

1. The IHC repairs itself (even in the presense of the damaging glutamate), thus a normal response to the PANs begins again (the hope for AM-101).
2. The IHC is killed, thus giving no predictable response to the associated PANs.
3. The IHC is damaged, thus giving an improper response to the PANs.

For those in case #1, the perceived tinnitus may disappear as the cell will be giving a proper signal to the CAS.
For those in case #2, the perceived tinnitus may very well remain for this reason: The signal coming from the IHC along the associated PANs is now gone, but, the CAS is looking for a signal, since there is still electronic noise, the CAS increases the gain of this signal until it has something to process.
For those in case #3, the perceived tinnitus is still being triggered by some incorrect mechanical response of the IHCs.

Obviously, case #1 people are very lucky and they are in a good position. To me it seems as though both case #2 and case #3 people have the same issue, the CAS is dealing with unexpected input. Either way, there is stimulus external to the CAS causing the tinnitus, and the CAS needs to deal with it. For people in case #2, their tinnitus mirrors the Heller and Bergman experiment (random noise increased by the CAS). For those in case #3, their tinnitus is similar to those with objective tinnitus in that IHCs are actually providing some undesired signal to the brain.

As I mentioned earlier, I believe the excess glutamate will stop eventually, in any case, and I believe this is why Auris is skeptical regarding the use of AM-101 past the acute phase. If there is no glutamate to block from the NMDA receptors, then there is no use for AM-101.

Once past the glutamate storm, it seems a solution will need to somehow stop the CAS from performing its amplification of the undesired tones. In either case, 2 or 3, it makes sense to believe that this amplification is affected by the limbic system, as it is clear that for most people, their tinnitus fluctuates with their anxiety / mood. Also, it seems that changes to the inner ear do not occur often, as it needs to be a stable environment. If even for a few moments, you notice that tinnitus volume has gone to a bearable level, this would imply that the CAS is capable of filtering out this sound to the point of comfort, and thus gives a reason to believe in the principles of tinnitus retraining therapy (TRT).

Many people on the forum seem somewhat anti TRT though, and I believe it may be due to a lack of belief in its principles. I have noticed that there are a number of people on the forums that define a solution to be one where their tinnitus becomes inaudible. The problem, is that regardless of the person, on average, tinnitus will become present in a completely silent room within just five minutes (the Heller and Bergman experiment). This means that for most people, the normal world is providing enough sound enrichment to keep their CAS happy. So, I think it’s important for anyone perceiving tinnitus to understand that it is a normal function of the CAS, and one which should not be looked at with such a sense of finality. Even my girlfriend started to develop some mild tinnitus after hearing me talk about it so much! She has absolutely no hearing loss, yet while trying to sleep the other night she was disturbed by a ringing. The point is, tinnitus may be triggered by an explicit event, like noise, but after the acute period, the signal being sent to the brain by the IHCs is likely non-existant, meaning that the CAS is now fully responsible and increasing the gain.

To me, the big elephant in the room is the problem with case #3. In this case, I know that the CAS is responsible for the gain of the sound, but to what degree? If there were a physical issue with the IHCs which causes them to vibrate uncontrollably, then it seams the brain would have a harder time adjusting than it would to no signal / random noise alone. Clearly, in cases where tinnitus persists after a cochlear implant / cutting of the auditory nerve, the persisting tone is something which is now caused by electronic noise, and not improper mechanical function.

Questions

So, I am wondering, does anyone know more about the mechanical operation of damaged cilia? If I knew for certain that my tinnitus was fully internalized to the CAS, I would have a much more belief in TRT. Although in either case, it helps to know that TRT has shown positive results for those with objective tinnitus as well. This leads me to believe that the CAS is capable of lowering the gain of signals which are not just random noise.

Also, if the primary purpose behind AM-101 is to give the IHCs more time to live / repair, then could not AM-101 be used to treat noise induced hearing loss (NIHL) in the acute stage as well?

Thank you for reading and I look forward to comments =)

 

You are making an assumption that AM-101 is effective. I think the jury is still out on that as the procedure and drug compound is undergoing Phase III trials. There are theories on how it operates, but its effectiveness in Phase II studies were not exactly conclusive.

 

Yes this that is true, in the post I was going through the theory as it has been given in the AM-101 publications. I think much of the theory can be separated in part from the effectiveness of the AM-101 trials though, as there have been many publications regarding the function of glutamate after trauma to the inner ear. It's a good point though, I wonder what we may uncover regarding the legitimacy of the theory as phase III is completed.

 

@Veita by "normally unused," does this mean those NMDA receptors typically have no role? I'm wondering, if a healthy ear with no tinnitus was treated with AM-101, do you know if there would be reason to suspect any notable side effects? Curious because I'm considering the AM-101 trial and I only have one ear with bad T, the other has very mild T. Do you know if the drug could block too much glutamate (being that there isn't really a "storm" going on in my good ear?)

 

I was a participant for the trial, but I backed out because my doctor agreed that steroids were the better option at the time. I regret the decision, but in the process I did learn that you will have the choice of which ear to choose. So, they will specifically ask which ear you prefer the injection (bi-lateral is fine too). As far as I know though, the NDMA receptors do not play a role (from what I've read), so I have no reason to believe the drug would cause an issue to a healthy ear. I obviously cannot guarantee this though, but if I were you, and I had the opportunity to do the trial, I'd do it in a heartbeat.

 

Interesting @Veita . I'm wondering how long this glutamine 'storm' usually takes? 1,2,3,4,5 months? It's an important factor.

I can imagine that from day 1 the cortex is already leaning to overreact and constructing a chronical circle. I noticed for my own T, the last week seems like double the volume. That must be coming from the cortex/brain activity. AM-101 is not gonna stop that right?
Wouldn't it be easier to take some trobalt until the glutamine storm settles? Trobalt can provide immediate soothing of cortex activity right, so then what would be the advantage of AM-101? The only one I can still see is that it relaxes the auditory nerves themselves from the excess glutamine uptake. So leaving your auditory nerves intact. But after like 2/3 months of waiting for AM-101, I wonder how many died already ... and if it's still usefull.

 

A couple of hours at most. This is why steroids can be effective in a small timeframe. The problem is when the excess glutamate triggers a cascade of events that ultimately leads to apoptosis. Supressing the immune system stops the induction of cellular death.

 

Ok @Nucleo. So apoptosis of the hair cells you mean? Since I read somewhere on this forum that AM-101 would save the auditory nerve from dying off? They talk about the glutamine storm as if it goes on for months. So if the storm is within hours, then I wonder how I have to re understand how AM-101 is supposed to work.

 

The glutamate storm in itself doesn't last very long. The damages it does however keeps going on for a while as other pathophysiological processes are activated. If AM-101 is administered somewhere during that time, it should prevent some of the nerve cells from dying, and indeed it does based on preliminary results.

 

@Veita

Would you recommend be part ot the AM-101 trial even with correct STD Audiometry? (up to 8Khz)

Do you think AM-101 have something to do with Stress/ATM/neck-related tinnitus?

 

Yes.

Absolutely not.

 

I have a very tought decision then, because my T is unknown, but:

-My T didint get lowered after ATM/Neck/stress treatment, so.... The cause must be 80% acoustic trauma or otitis media, do you think like me guys?

 

I read somewhere that the nerve "healing"/reconnection to IHC takes about 5 days in mice. Perhaps that's why the injections for AM 101 occur over 5 days. As long as the glutamate storm is quelled for this healing time, there can be recovery (is what Auris Medical is presuming, I believe).

 

I'm definitely going for it!

 

Well @OddV got his best results with injections 8 months after T onset, so here's hoping!