Thank you for joining us. Can you introduce yourself? How did you decide to pursue your education and current role? 

Sure! I’m Megan Beers Wood. I have always been interested in science and specifically the immune system. For a long time, I wanted to be a medical doctor. However, in college I got the opportunity to perform immunology research for the first time and decided that translational science was my goal. I went to graduate school at Emory University. 

The reason I was so interested in immunology is due to being diagnosed with Juvenile Idiopathic Arthritis at the age of 2 by an immunologist. When I was in graduate school, I studied an epithelial cell in the intestine called the M Cell that interacts with the immune system. These cells require some of the same signals for development as the hair cells in the ear. 

However, intestinal epithelium regenerates every three days and hair cells do not regenerate. That is what initially attracted me to the ear! 

Once I started working in the cochlea, I was fascinated by such a complex tissue that has a beautiful structure where neurons and epithelium work closely together – and immune cells are everywhere in the cochlea! 

My postdoc at Johns Hopkins with Drs. Paul Fuchs and Elisabeth Glowatzki has taught me a lot about the neuroscience of the inner ear. They have been working to understand these type II afferent neurons in the inner ear that look like pain-sensing fibers. That has been one of my major projects. 

Along the way, I met Bryan Pollard and became more and more interested in studying pain hyperacusis. My current role is Research Associate after I was promoted last year. 

Congratulations for the promotion! What is your current research focused on? We’ve heard you are planning to start your own lab. Can you (publicly) share more information about this? 

Thanks! I am on the job market right now. My lab will be studying the interactions of the immune cells and neurons of the inner ear. One model I hope to use is painful hyperacusis. So, I have been working on a way to study painful hyperacusis in the lab. 

I was awarded a grant from the Hearing Health Foundation to start creating this assay. Basically, we will use the analysis of facial features of lab animals to assess whether they perceive pain while they are listening to sound that is not normally painful. 

Your presentation about that at the Iowa conference was very cool! Are there any updates on that work since then? 

Thank you! We have continued fine-tuning the AI used to help us measure facial features. Specifically, we have improved eye tracking. We have also analyzed more mice. So, we do feel we can measure at least four changes in facial features associated with pain. This is the first stage to test whether our assay can work. I should say that our assay can work to detect pain related to an auditory stimulus. 

Sounds like wonderful progress! 

Thank you! I am working with a very gifted undergraduate student to do this work. 

In your studies, CGRP antagonists were administered prior to noise exposure. Do you hypothesize that administration after noise exposure may in some way treat pain hyperacusis? Some patients who have tried CGRP antagonists have reported varying degrees of improvement of their pain and loudness hyperacusis. 

I think that would be an interesting area to study. However, in the lab we would need a working model of painful hyperacusis to do a properly controlled study. This is one reason I have been working to develop a method to test the perception of auditory pain. The CGRP study is ongoing and was designed to test the effect of CGRP on immune cells in the cochlea. 

In the ear, we still do not understand the function of CGRP. It is well known in other parts of the body to be necessary for pain perception and for interacting with the immune system. So, I guess the answer to your question is: I do not know whether CGRP antagonists could treat hyperacusis. 

Can anti-CGRP drugs such as the one used in your studies penetrate the blood labyrinth barrier? 

I specifically chose the small molecule antagonist of CGRP as there was data to suggest it crossed the blood brain barrier (BBB). The reports on the antibody antagonists for CGRP were mixed about their ability to cross the BBB. 

Very interesting! That makes sense. From your perspective, how do you think ototoxic medications cause pain hyperacusis? Is the mechanism the same as for noise-induced pain hyperacusis? 

That is a wonderful question. There are differences in the damage caused by ototoxic drugs vs. noise injury. 

Basically, some ototoxic drugs seem to cause cell death of hair cells whereas noise injury causes mechanical damage to the hair cells and can cause excitotoxicity in the neurons of the inner ear. 

Both types of damage can cause an immune response. So, I guess this gets back to a larger question of: Is all pain hyperacusis caused by the same mechanism? 

At this stage, we don’t know. 

Hopefully your research can bring us closer to the answer. Can you tell us about the time course of cochlear damage after acoustic trauma or ototoxic drug exposure? In some patients, hyperacusis seems to continue worsening for weeks or months before stabilizing, even without further damaging exposure. 

I can attempt to summarize the tissue damage after noise exposure, but I am less sure of the time course after ototoxic drug administration. This is because, I believe, the mechanism of damage to the ear is different from platinum agents vs. aminoglycoside antibiotics. Platinum agents appear to be retained in the ear for a very long time. 

For noise injury, the amount of damage typically depends on the intensity of the noise exposure. After the initial exposure, the stereocilia on the hair cells are in disarray. The outer hair cells may not die immediately, but over the course of several days. The synapses between the inner hair cells and neurons will be affected immediately and undergo some repair over the first week (if possible) after the noise (this is all based on mouse studies). If some neurons die completely, their cell bodies will not be gone until several weeks after the noise exposure.  

Now for the immune response: 

The macrophages in the ear will migrate to the synapse between the inner hair cell and the type I neurons immediately. Then, immune cells will be recruited into the ear over the next several days lasting for at least two weeks. All of this is assuming the noise exposure was bad enough to cause you to have a permanent hearing loss. 

When a noise exposure is less severe, less damage occurs. 

We also have to remember that the frequency of the sound is also important and that the base of the cochlea where we hear high frequencies is the most vulnerable to damage. 

All of this to say: the tissue damage and response to tissue damage does not stop when the noise stops.  

This question is one reason why I am interested in studying the immune response as a possible mechanism for hyperacusis. 

Do you have any theories as to why some cases of pain hyperacusis improve without treatment or resolve while others do not? 

I think this is an interesting question. I can think of three possibilities: From some comparative studies in animals and humans, it does appear that humans can withstand some types of noise exposure better than other animals. So, it is possible that if painful hyperacusis is linked to a resolution of tissue damage that would be one explanation for hyperacusis going away with time. It is also possible that for some people the brain learns to compensate for whatever caused painful hyperacusis and deems the perception of pain no longer useful. Third, if pain hyperacusis is tied to an inflammatory response then the way that person’s ear immune system responds could perpetuate symptoms. These are educated guesses. 

Very interesting theories! Some patients mention that their setbacks worsen them permanently even when caused by a sound that would not be damaging to the average person. Do you have any ideas about why that might be? 

The description of setbacks is the reason I am interested in an immune-mediated mechanism of hyperacusis. Much like the flare cycle of symptoms in autoimmune patients and the recall response of immunity in the reaction to a second round of a pathogen, I have wondered if a similar mechanism is happening here. In other words, is the immune system primed to respond when it shouldn’t? 

If this turns out to not be the case, then at least we would have eliminated one possible mechanism for hyperacusis. 

Speaking of autoimmune disorders, many pain hyperacusis patients also have comorbid inflammatory/autoimmune conditions. Could treating underlying conditions assist in recovery from pain hyperacusis? Does the immune-privileged status of the inner ear affect this? 

I think we need to have a better grasp on just how many people with pain hyperacusis have immune disorders whether they be autoimmune or even allergy. It’s possible that the blood labyrinth barrier may prevent some biologic drugs (antibodies) from affecting the ear although I am not aware if this has been shown. It may be that treatments that can be delivered to the inner ear need to be developed. Luckily, there is ongoing work in this space. Of course, drug delivery to the inner ear of a hyperacusis patient would require sedation. 

I think it is possible that the protected nature of the inner ear may create its own immune response separate from the rest of the body on occasion, making it hard to treat. 

Some patients have successfully treated their pain hyperacusis using diets that are low histamine and/or carnivore (some maintained the diet for a period of months, some maintain indefinitely). From your perspective, could this approach work for cases of pain hyperacusis of cochlear origin? 

I did not know that people had tried dietary changes! Changes to the diet could reduce inflammation in the body systemically. There is some research on histamine in the inner ear and there are certainly mast cells in the inner ear. I would view this as being similar to taking an oral steroid, it can reduce inflammation everywhere which may reach the inner ear. Whether it would work on a specific mechanism, I am unsure. 

What are your thoughts on the middle ear theory of pain hyperacusis presented by Noreña et al. (2018)? 

I think this is one area where we need to have better diagnostics of ear pain. It is possible that painful hyperacusis comes from the middle ear and that the facial pain that some people experience is related to this. I think it is also possible that some people have pain hyperacusis that comes from the cochlea itself. I think all possibilities need to be studied simultaneously with the hope that people with hyperacusis get answers faster. 

We couldn’t agree more! We actually have a question somewhat related to that. Is there a way that cochlear noxacusis could cause pain in the ear canal, outer portion of the ear, face, scalp, or throat? 

I am not aware of any mechanism. 

Is there an explanation why some patients experience immediate pain versus delayed pain? 

I am also not sure of that, but the delayed pain is something we want to try to study. 

That would be very interesting. Do you think hair cell regeneration would improve or cure pain hyperacusis of cochlear origin? Why or why not? 

Interesting question! I’m not sure. I think that if painful hyperacusis is caused by damage to the ear, then that is possible. If it is spontaneous, I am not sure that hair cell regeneration would help. 

It has been shown that the stria vascularis can be damaged by exposure to loud noise. Could you explain the implications of this?  

One of the most important roles of the stria vascularis is setting up the ionic concentrations needed for the hair cells to communicate with neurons. An imbalance in these ionic concentrations can affect the hair cell:neuron synapse. Damage to the stria vascularis can happen with noise exposure and age. 

Do you think there may be some overlapping mechanisms between loudness hyperacusis and pain hyperacusis?  

I think that is possible. With further surveys of patients and better animal models, we can hopefully answer this question. It could be that they are independent conditions, and it could be that loudness hyperacusis could precede pain hyperacusis. Right now, there is good evidence that loudness hyperacusis is mediated by the brain amplifying sound signals that it shouldn’t – this is called central gain.  

One patient recently reported an improvement of pain hyperacusis symptoms after a sphenopalatine ganglion (SPG) ablation followed by SPG blocks. From your perspective, what do you think might be the mechanism of this improvement?  

It looks like SPG blocks have been used in the treatment of migraine. If painful hyperacusis is a form of auditory migraine, then this treatment could help. Other than that, I’m unsure of the mechanism.  

We know that there is little funding for hyperacusis research, especially for pain hyperacusis. What are the biggest challenges you have experienced in getting funding for your research? In addition, you are on the scientific advisory board for Hyperacusis Research. Can you tell us about that involvement and what you are hoping the organization can achieve over time? 

One difficulty with studying a condition such as pain hyperacusis is the relatively small amount of research that has been done. Funding agencies typically want to fund grants for research that has a high degree of success. With hyperacusis, so much is unknown that a well supported research plan is hard to put together without extremely convincing preliminary data. Collecting preliminary data has to be funded. So, this becomes a circular problem. Grants like the Emerging Research Grant (ERG) through the Hearing Health Foundation (HHF) can help overcome this problem. Hyperacusis Research has helped fund Emerging Research Grants through HHF. This allows researchers to collect preliminary data for early publications and to write proposals for larger grants. This is just one way Hyperacusis Research is helping to increase overall hyperacusis research. As a recipient of the hyperacusis-focused ERG grant from HHF, I was invited to attend board meetings and now I am a member of the board. Hyperacusis Research has increased their fundraising and is looking to continue funding more grants. The Scientific Advisory Board is working to help increase awareness of this topic by hosting a dinner at ARO in 2024 and by providing reviewers for grants. I am hoping that we will be able to increase research interest and continue to provide more grants for researchers in the years to come.  

We are aware of the existence of the National Temporal Bone Registry. Do you know if the function of type II afferents has ever been investigated in human postmortem studies, especially in patients with pain hyperacusis? 

Temporal bones preserved through the National Temporal Bone Registry and institutional temporal bone repositories are the reason that we know type II afferent neurons are long-lived in humans even after outer hair cells are lost. Depending on when the temporal bones are retrieved after death, functional studies of type II afferents may be difficult. However, imaging of type II afferents can be done and compared between those with reported hyperacusis and those without. This could help us test whether some of the same proteins we are studying in animals are relevant in humans. To my knowledge, a specific study on hyperacusis has not been done.  

Thank you again for this interview!

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