What is your current research focusing on more specifically?  

One aspect is how the different cells of the cochlea are formed. This has allowed us to genetically swap the position of, for example, inner vs outer hair cells. And this is permitting us to perform previously impossible experiments with which to elucidate how the cochlea gets wired up and connected with the brain. This is giving us new animal models in which to test what each type of nerve connection between cochlea and brain is doing. This is the work that we hope will prove relevant to pain hyperacusis.  

That’s fantastic! How does your pain hyperacusis research differ from that of Fuchs and his lab?  

We use complementary approaches. They study one cell at a time, whereas we study whole animals with genetic modifications. For example, we disabled the normal way of communication between the cochlea and brain and found that the brain of these mice would still respond to noise, but only of a harmful intensity, of the kind that killed outer hair cells in the cochlea. Our approach pointed out type II afferents being the ones mediating this communication (or harmful noise), which we called auditory nociception. The Fuchs lab had developed a method for recording the activity of single type II afferents, and they found these neurons responded little to noise. But now they went back to their single cell examinations, killed a single outer hair cell, and saw a whopping response by the single type II afferent neuron connected to it. This pretty much proved that type II afferents can respond very robustly to hair cell damage. They called this phenomenon noxacusis, which I take for an elegant synonym of auditory nociception.  

The point is that the field benefits from labs addressing the same overall question with different techniques, and we can use results from each other to design better experiments 

That’s very interesting! We’re glad that different researchers are exploring different avenues. What are your thoughts about the relationship between loudness and pain hyperacusis? Some patients have reported a slow worsening of loudness hyperacusis that eventually turns into pain hyperacusis even without any further noise damage or ototoxic exposure.  

I really don’t know. But the simple idea of a pain-like system for the ear is that, just like the pain systems everywhere in the body, they normally report tissue damage or stimuli threatening to cause it. However, in conditions such as neuropathic pain and allodynia, non-harmful light stimuli are pathologically reported as painful. This is what could be happening in pain hyperacusis, either through the type II afferents or through other neurons.  

Similarly, do you feel that there is a link between tinnitus and loudness and/or pain hyperacusis?  

That is too complicated for me to speculate on right now.  
My gut feeling is that they are probably related, but I have no specific evidence to state it right now. 

No worries, it’s probably a complicated relationship. Could noxacusis resulting from the type II afferents cause pain in the ear canal, the exterior portion of the ear, jaw, neck, or throat, as is reported by many pain hyperacusis patients? If so, what do you think is the mechanism behind this? 

It seems less likely that cochlear nerve activity would trigger the sensation of pain in the middle ear and ear canal. But it could result from referred pain. Internal pain is not generally well localized, and often a nearby structure hurts that is not damaged. Something of the sort could explain it. The other is to see the cause not in a cochlear nerve, but in the trigeminal innervation of the middle ear.  

That makes sense and also leads us to our next question. What are your thoughts on the middle ear theory of pain hyperacusis presented by Noreña et al. (2018)?  

I am not an expert on the middle ear, but it seems a very reasonable area to examine. In our study, we ruled out trigeminal innervation (of the middle ear) as likely to explain the brain activity caused by harmfully loud noises in deaf mice. But what happens in pain hyperacusis patients may be different. We still don’t know. Both inner ear and middle ear involvement should be studied further. 

We agree with that! In “normal” human ears, pain is felt from sound once it reaches 130dB or so. What do you think is causing this pain?  

I am not familiar enough with the middle ear to know whether its trigeminal innervation would be activated with 130 dB. I know that lots of hair cells, particularly outer hair cells, would start dying, spilling their contents into their surroundings and that the type II afferents would be firing up in response. Whether that causes a feeling of pain we still need to figure out.  

Some noxacusis patients have primarily immediate pain from sound, while others have delayed pain. Which do you think is more likely to be evidence of inner ear noxacusis? Do you have any theories as to what might explain this difference?  

I don’t know. Both could result from sensitization of the nerve, whether auditory or trigeminal. The delayed response may involve a subsequent reaction from the brain. It is all very speculative.  

By the way, the trigeminal nerve does not innervate the cells in the cochlea proper, but it innervates the blood vessels irrigating the cochlea. Something similar happens in the brain. They (trigeminal neurons innervating vessels) could also participate in pain hyperacusis or some form of earache, as they do in headaches. 

That’s very intriguing. Do you have any theories as to why some patients seem to recover from pain hyperacusis over time while others do not?  

I have no theories regarding differential recovery. 

The following questions are in reference to your 2015 paper entitled “A Non-canonical Pathway from Cochlea to Brain Signals Tissue-Damaging Noise.” Theoretically, do you think the VGLUT3-/- knockout mice* could develop a sort of hyperacusis and exhibit neuronal activity in the cochlear nucleus in response to lower decibel levels (for example, 70dB) after exposure to long periods of damaging noise?  

In theory yes. The idea would be that neurons detecting damage to hair cells in a VGLU3-independent manner (probably not involving the glutamate neurotransmitter) have been sensitized and now respond to light (low intensity) sound stimulation.  

Wow, that is interesting. Is there evidence yet that the neuronal activity in the cochlear nucleus (CN) in VGLUT3-/- knockout mice could be felt as pain?  

No, we have not proceeded with those experiments yet. But we intend to.  

Basically, the neurons in the CN would not themselves cause pain or any other conscious sensation. The signal, the neuronal activity, would have to be transmitted to parts of the brain underlying conscious sensations, such as the cerebral cortex.  

Great to hear that! Since you’ve shown that type II afferents project to the dorsal cochlear nucleus (DCN), is it possible that devices designed to decrease overactivity in the DCN (such as the device designed by Susan Shore at the University of Michigan) might help in the treatment of pain hyperacusis?  

It is very early to tell. But we found that type II afferents likely activated neurons all over the CN, not just the DCN. In fact, it is the regions between the DCN and the VCN, the so-called granule cell region, that are exclusively innervated by type II (and not I) afferents.  

Basically, in addition to more selective and alternative ways to silence type I afferents (leaving type IIs intact), we must also eliminate or silence type II afferents alone. Then the results will be much easier to interpret. 

In the last sentence of the paper, you say “future studies aimed at eliminating the VGLUT3-independent auditory sensing here described (perhaps through ablation or inactivation of type IIs) could resolve the issue of whether this form of auditory nociception contributes to nocifensive behaviors.” Can you tell us a little more about this and anything else you are hoping to investigate in future noxacusis research?  

This is where we are now. Developing ways to selectively target each neuronal type alone, or in combination, to determine which one transmits what type of information (particularly harmful noise) to the brain. And then, elucidating what parts of the brain beyond the cochlear nucleus get activated. Do loud noises in a mouse with blocked normal auditory neurons trigger activity in brain areas that signify pain, such as the amygdala? 

We are very much looking forward to that research! Do you believe that hair cell regeneration could help with treating noxacusis? Why or why not?  

In principle, I doubt hair cell regeneration would help, as I don’t know that the loss of hair cells is involved in pain hyperacusis. This I think is good news, because regeneration could be a long way ahead of us. On the other hand, once we know what type of neuron transmits pain hyperacusis, one could search for ways to block them.  

How long do you think it will be until hearing regeneration in humans is possible and available? What do you see as the major roadblocks that must be overcome to achieve this?  

It is hard to tell. There is progress in figuring out how to make hair cells from supporting cells, and our contribution is figuring out how to specifically make inner versus outer hair cells, since they play complementary roles and replacing one with the other would hamper, rather than restore, hearing. The remaining roadblocks include making this regeneration occur in the adult (thus far it occurs from very young, but not adult, supporting cells), getting the new hair cells appropriately aligned and encased with supporting cells (this is particularly relevant for the OHCs), and getting them re-connected to the brains (i.e., re-innervated by the auditory neurons; this is crucial for the IHCs, which are the ones mainly communicating the detected sound information to the brain). We are working on most of these hurdles. Our goal is to overcome them in experimental animals (mainly mice) within the next decade. As we find out how these phenomena occur during normal mouse development, we will try regenerative attempts in mice. Only when a study in animals shows significant restoration of hearing would it make sense, in my opinion, to attempt something in human patients.  

Technological progress is unpredictable. As we try to overcome each of these barriers, we will see how difficult it is for the next. For example, if the new hair cells get spontaneously re-innervated, then a potential therapy gets closer. If they are not, then we have to figure out how this is done and try reproducing it.  

It’s great to hear we are making progress through various discoveries including the ones in your lab. You mentioned that after further research one could search for ways to block auditory nociception. What might this treatment look like? Could an existing compound achieve this or would a new one likely need to be developed?  

Once we are certain of what neurons to target, and given that we know already a lot about what genes each neuron type uses, then we could see if any available drug targets the products of those genes. Drugs like ion channel blockers or activators, which would alter the excitability of the neurons. They may already be on the market, just not tried (for auditory nociception or pain hyperacusis). If this is not the case, then a proper screening for new drugs would be needed. 

Hopefully, currently existing drugs will be able to help. In theory, do you think that cutting the auditory nerve would eliminate auditory nociception?  

I would be very cautious. I believe that cutting the normal pain fibers may not prevent the pain and could cause phantom pain. In any case, you would want to cut, or disable, the neurons carrying the painful sensation, not the ones detecting normal sounds. 

Very good advice. At least one patient’s noxacusis symptoms were significantly improved by a sphenopalatine ganglion block (SPG block). In your opinion, what would be the mechanism behind this improvement?  

I would have to read about this before formulating an opinion.  

We understand that. Some ENTs, including Dr. Bance in the UK, have had success treating pain hyperacusis with tympanic neurectomy (cutting Jacobson’s nerve). What are your thoughts about this?  

Again, I would have to look at these papers. It would take me time. And it would fall out of my area of closer expertise. Other experts would be better able to assess the validity and credibility of these reports.  

No worries at all. Although your focus is research, do you have any advice for pain hyperacusis patients whose healthcare providers do not believe their symptoms or their severity? Sadly, this is quite a common situation encountered by patients. Patients are often told that “everyday sounds can’t hurt you” even though their condition has worsened from exposure to everyday sounds.  

I find this very frustrating. Doctors with knowledge of pain hyperacusis and patient organizations should publicize this condition and get the wider medical community aware of it.  

I am not in a position to influence public perception on this topic as I don’t examine human patients, and what we examine in mice is their neuronal responses to loud sounds, not pain hyperacusis caused by low-intensity sounds.  

Hopefully, we can contribute to that! We would like to thank you again for participating in this interview and answering all of our questions.  

I am glad we talked!  

*A knockout mouse is a laboratory mouse in which researchers have inactivated, or “knocked out,” an existing gene by replacing it or disrupting it with an artificial piece of DNA (from https://www.genome.gov/about-genomics/fact-sheets/Knockout-Mice-Fact-Sheet) 

In these particular experiments, VGLUT3-/- knockout mice were unable to hear sounds via the type I afferents. However, their type II afferents remained functional.