Lenire: Tinnitus Review For Bi-Modal Stimulation

Ben Thompson, AuD.

Every so often the world of tinnitus has new research developments. One of the newest research developments in tinnitus is something called bimodal neural stimulation. And today I’m here with Dr. Hubert Lim from University of Minnesota. Dr. Lim is a professor of biomedical engineering and otolaryngology specializing in the hearing systems. Dr. Lim, tell us more about your research and a little backstory about what you do.

Hubert Lim, PhD.

Yeah, well, first of all, thank you Ben, for having me. I watch your YouTube station and you’re doing an amazing job at really getting information out there. And I know it’s not easy keeping up with this, so thank you so much. And I do appreciate the opportunity to share. So I am faculty at University of Minnesota, as you mentioned. And there, I’ve been there since 2009. A lot of my research has focused on hearing devices. So those could be restoring hearing like cochlear implants or hearing implants, but also ways to treat tinnitus, as you know, this podcast or this YouTube video today will go over. And I’ve been approaching it quite a bit using non-invasive approaches.

My lab we’ve looked at things like electrical fields, magnetic fields, ultrasound fields, and how we can alter coding in the brain to try to reduce the symptoms of tinnitus. So that’s a lot about what my lab does. In terms of what I’m interested in and how I’ve gotten to be interested in tinnitus is that early on in my PhD career at University of Michigan, I was working on ways to stimulate the auditory pathways. And I discovered quite a bit of, just out of luck, that you could stimulate different pathways, not only in the auditory system, but in the non-auditory system, right, so like your somatic sensory system, and be able to alter coding in the brain. This was in animal experiments. And also if you combine modalities, you could actually lead to long-lasting plasticity or changes in the brain. And so that is where I thought, if this can actually work, maybe we could apply this to something like tinnitus, where there just hasn’t been, you know, there are opportunities and options, but there just hasn’t been as much treatment options available that are consistent and effective. So that’s my entry into tinnitus was through my PhD going into my postdoc, but I’ll pause there for other questions.

Ben Thompson, AuD.

Thank you so much. Thank you so much. You’ve done some work on the different nerves that are in the neck, different nerves that are on the tongue and how that can affect tinnitus and hopefully improve it, reduce the volume or the intensity. Now, a question for you. For someone who’s relatively new to tinnitus and probably doesn’t know too much about bimodal stimulation or these different treatment technologies and research, can you give us in a few minutes, an overview, let’s say the last 15 years, what have we learned about the brain and tinnitus and potentially leading to tinnitus treatment technologies?

Hubert Lim, PhD.

Sure, sure. Maybe since most people are familiar with hearing approaches, right, like sound master, sound therapy, I know if you look at some of the clinical guidelines, right, and some of the reviews that they do, they’re not saying that hearing approaches are clinically recommended. I mean, I think Ben, you know this, we all know this, that it doesn’t mean it doesn’t work. It just means that the data out there, the way the studies have to be done. So we do know that hearing approaches can be effective. And some of what happens there is you play sound and it’ll interact with those cells, right, in your brain that are coding for the tinnitus, and it’ll kind of interrupt them or disrupt how they’re functioning, and that helps relieve some of the tinnitus sound or the tinnitus symptoms. And then even in cases you could play sound, and it’ll actually alter the coding enough that when you stop the sound, you have some relief residually, right. So that already tells you that sound alone can already interact with the tinnitus cells acutely, or even somewhat residually. Usually it’s not long-term, but there’s some benefit there, right. So I want to put that out there so people can understand what’s going on with sound. When you think about bimodal neuromodulation or bimodal stimulation, it’s two inputs, right. so bimodal, two modalities.

And even though, which we’ll talk about later, my lab and also the company I’m involved with Neuromod Devices, we’re using specific regions like tongue simulation or electrical ear stimulation. Even though we use those, it doesn’t mean that it’s limited to just those inputs. We’re talking about bimodal in general, right? So it could be sound with tongue stimulation, sound with electrical ear. It could even be sound with, you’ve seen these magnetic coils that they stimulate in the cortex. You could do that as bimodal, right? But now why bimodal? So this isn’t something that lasts 15 years only. But if you go way back to Pavlovian conditioning more than a century ago, you know about the Pavlovian Dog. I like to tell this story because it does really help make it more tangible in what’s going on. You know you have a dog that is hungry, and food will be brought to the dog and the dog will salivate. Now what you could do is you could play a bell, a sound, and that sound is meaningless to the dog. But then if you play the bell, and you provide the food at the same time, and that the same time is perceptually, it could be on seconds, it could be on milliseconds, but you provide those at the same time, the brain starts to create meaning to that bell, that sound. And so now when you don’t present the food, then already if you just present the sound, the dog salivates. And that already shows you that the brain can be rewired to become sensitive to, but in the same way, not sensitive to other sounds. And it really is about this kind of reinforcement of the sound information, right? Now, what has happened in the last, I would say even 20, 30 years, is there’s been so much research done in animals, some in humans, but in animals, where they actually started to pair things together. They would pair tones, frequencies, with body stimulation. It could have been shock on the leg. It could have been electrical stimulation of the vagus nerve. It could have been electrical stimulation of the trigeminal or face. And you could actually show that by pairing those together, you could start to change the coding in the auditory system, not to say you couldn’t do it with sound alone, but when you did it with bimodal, the changes were much greater, or I won’t say much bigger, but definitely greater, significantly greater. And so that already tells you that things can change in the brain. You do this bimodal stim. Now the question of course, and this is where in the last 10 years has been very exciting. My lab at University of Minnesota, Neuromod Devices, Dr. Susan Shore’s lab at University of Michigan, multiple other groups are trying to figure out what are the right parameters of this bimodal stim, and which inputs, which body regions, what sounds that will actually perturb the most, those tinnitus cells, right? Whether it’s, and we can get to this a little bit later, but whether it’s to shut those cells down, or to make other cells more active, so then the tinnitus cells are less important. Hopefully that gives a nice picture of what bimodal neuromodulation is, or bimodal stimulation.

Ben Thompson, AuD.

Absolutely, and from my training, from my study with Dr. Jastreboff, TRT, tinnitus retraining, one of the major takeaways is, from what I know, from how I communicate with patients, that the neuronal activity, the cells around the tinnitus, the phantom sound response, those cells might not change so dramatically much. But the filter mechanism of the brain specifically via attitude, reaction, emotion, can affect our waking experience and perception of the sound. This is something that can be very complex, and I’m sure you know micro details of this that I would never need to know, what is your opinion on when tinnitus gets softer or less bothersome, what is happening at a brain level?

Hubert Lim, PhD.

Yeah, and you’re right. It’s quite complicated because, your question is about loudness perception. I like to think of it as in two portions. One is the loudness of the sound. Now that loudness of the sound could be sound coming into your ears, right? For tinnitus case, it’s a sound being produced somewhere in your auditory pathway, right? And there’s a loudness to it. Then there’s the perception, awareness of the sound component. And those together make up the loudness perception, right? Now, to just get more tangible example for your audiences, I love my kids, a disclaimer here, but I love my kids, but they can be quite loud. But amazingly when I’m working on something and I’m really deep in thought, sometimes I don’t even realize that they’re being so loud in the background, and then suddenly something will happen that’ll trigger me to then pay attention. And I’m like, “Oh my goodness, they are so loud.” So how can that be that they’re so loud, but my brain has just filtered it out to your point. So it tells you that loudness is not just the loudness of the sound, it’s your brain also, it’s awareness and the way it’s perceiving that sound. I want to bring that up. And the reason why I bring that up is because there are cells that are definitely coding for that sound. We know that from neurophysiological, auditory physiological experiments. But if you go higher up, and even, I would say midbrain cortex, we’re finding out that that is able to code awareness. But you go into the different cortical regions, like your frontal lobe area, some secondary cortical regions, and the perception is happening, right? So this gives us two ways to tackle the problem. One is you could try to figure out how to interact with the loudest portion, and/or interact with the awareness portion, and I do believe that both are appropriate and effective ways to tackle it, right?

Ben Thompson, AuD.

Absolutely, and our main question is, can this technology that you’ve been researching get into the loudness component because that, if we solve this as a scientific community, it can affect so many people’s lives. Stress. Sleep.

Hubert Lim, PhD.

Yeah.

Ben Thompson, AuD.

Quality of life, even the amount of energy I have during the day, because when the sound is so much, people may feel that their energy is lower. So I wanted to ask you now, what is the success? Obviously the research wouldn’t continue on if there was not some promising results coming. What is the summary on the different research groups, what they’ve found, how are we measuring success and some details on that?

Hubert Lim, PhD.

Yeah, sure. It’s a very good question. How much can we reduce the loudness, also awareness? So my lab, since about 2009-10, I did do some hearing research, some plasticity work before then, but since 2009-10, my goal was to figure out how we could shut down the loudness of the tinnitus. That’s what I was quite interested in. And I did some initial experiments in Guinea pigs, where, you know, obviously you can induce tinnitus in animals, and you could try to create the perception. I wanted a more objective way to do this. So I would just play sounds to the animals. And then in the brain, in the auditory brain, you’re going to get cells firing, right, to that sound. And so they are coding for the sound. That is actually the sound being coded in those cells, right. And I wanted to see, could I use bimodal stimulation? Could I use sound beforehand, right, and then electrically stimulate the tongue, or the ear, or the body, or the neck, and then when I play that sound again, that it was heavily attenuated, meaning that I altered something in the brain that basically shuts down that loudness effect, right. And that’s what I was interested in. I will tell you, it was exciting ’cause we could do that. We could do it in animals, right. And it wasn’t just my lab. Dr. Susan shore, who you already know, and I don’t know if you had her on your YouTube channel, she has been a pioneer in this field. She definitely, since early 2000s, has been interested in looking at trigeminal, the somatosensory pathways, and sound to modulate the auditory pathways and see how it affects it, right. She also showed that if you did trigeminal stim, then later on in guinea pigs and humans, she did cheek or neck electrical stim with sound, she could actually find some patterns that at least in animals, right, that she could also shut down the loudness, per se, whatever you want to call the loudness, but that sound-driven activity, it could be suppressed down. So from that, you might say, “Well, let’s go for this approach of shutting down the tinnitus.”

Now, this is what I realized doing research in my lab after over 100 Guinea pig experiments, six years, six-seven years of research, trying to identify from animal to animal, and eventually from human to human, the variability that you have to shut down the sound that is specific to each individual. This is possible, but it’s going to take more research and more optimization per person. I’m not saying we can’t get there, but you’re trying to find those cells and shut ’em down, right. In my mind, I thought, “Does it have to be that way? Do we actually have to shut down those cells?” I mean, just the example with my children, who I love, I’m doing just fine if I could just shift my attention away from those sounds. So this is where in 2015-16 time, I kind of said to myself, and this was after we published in “Nature Scientific Reports.” It’s available on my website. You can look at the publication. We found encouraging results of doing that or shutting loudness coding, right? Can we make this a bit more generalizable, broad-reaching, right, where we don’t have to fit everything to each individual, that we could just more focus on shifting their attention. And this is where then I went back to not my research, but to research that’s been around for 30 years where they showed that you could make the brain more sensitive to a given sound. And that’s much easier to do ’cause you’re not focusing on trying to figure out what is the tinnitus, what are the tinnitus cells? You’re like, “Okay, I’m just going to try to make your brain more sensitive to one kilohertz. And how do you do that? Well, you play one kilohertz and you provide bimodal stim. In our case, it could be electrical stimulation of the tongue. They give you electrical stimulation of the ear, and you just do that over and over again. Now you don’t want to do that, ’cause you’re going to make them hear one kilohertz potentially, or overly sensitive to one kilohertz, but you make the brain more sensitive to one kilohertz. Then you do it for four kilohertz. Then you do it for eight kilohertz. Then you do it for 500 hertz. Ideally, you wouldn’t want to do it for the tinnitus sound, but it’s hard to identify that. You just need to have enough diversity. And in essence, you’re making your brain more sensitive to a lot of different things, and your brain can’t be ’cause, same thing we know we can’t multitask. We can’t hear 20 people talking to you and decipher what’s going on. Your brain ultimately, relatively speaking, has to downplay the tinnitus sound ’cause it’s got to get its mind focused on the new sounds that you’re telling the brain that is important. And so relatively speaking, your awareness is now diluted for the tinnitus sound. So that’s where I really got excited. Can we go in this direction? And that’s, and I know we’ll get to this, but with Neuromod Devices, this is where the CEO and myself, we really resonated, can we find a more broader approach? This is where we start to move towards is, can we really focus on the awareness and do it in a much generalized way?

Ben Thompson, AuD.

Thank you, and from the research so far, what is the timeframe of how many weeks or months in an ideal scenario, good compliance, knowing how to do these protocols, the right kind of patient. We’re not expecting dramatic shifts here of silence, “I don’t hear tinnitus anymore,” but improved enough to make it significant and worth the time. How much time would it take for some of this brain plasticity to take effect through the bimodal stimulation from what you’ve seen?

Hubert Lim, PhD.

Yeah, that’s a very good question. I do sometimes look over “Tinnitus Talk,” and I saw some comments where people are talking about a study that I did in my lab, a pilot study with some individuals, volunteers, who have tinnitus. When we try to optimize, we stimulate a lot of body regions, and we stimulate a lot of delays. And if you could find that perfect delay, that perfect body region, it was surprising because we could actually, within that single session, we were able, repeated 30 minutes or whatever how long we need to, we could actually suppress the loudness or the awareness residually for a certain amount of time, but it could happen quite quickly, right? So I think there’s some opportunities on that end, on the extreme end. That didn’t happen often, but there could be some opportunities there. Now what I’m doing now with Neuromod Devices, which is the company where I’m serving as chief scientific officer, we’ve run two large-scale studies. First one was 226 participants, and the next one was 190, 191. Through that study, I can say a little bit more in a confident way because we have enough individuals involved. We provided treatment to them, the bimodal stimulation, Lenire device, in Europe. And we saw that within about… The treatment is for 12 weeks. But we saw the majority by about six weeks, we’re already seeing this improvement, I won’t say in the loudness, ’cause it’s difficult to measure that and consistently, but we’re talking about tinnitus symptom severity. We do tinnitus handicap inventory or tinnitus functional index, both of them, saw consistent results, and that is assessing the symptom severity, and we saw improvements in their symptom severity within six weeks. Now, could it have been faster? We did have just anecdotal information of people saying that they felt something going on within the first three weeks, three to four weeks or something like that. We only took official data collection at six weeks. So all I can say with confidence is that by six weeks we’re seeing quite a bit of improvement in the majority of the individuals, but less than that it could be also, but the data, I don’t have that to make that claim.

Ben Thompson, AuD.

Well, first I want to say thank you for you and your scientific partners for taking your time to study tinnitus, so needed. And everyone in here in the community agrees. If you’re watching this on YouTube, please write underneath, “Yes. I agree.” Thank you, Dr. Lim.

Hubert Lim, PhD.

Thank you.

Ben Thompson, AuD.

And his team, and all the others working on this. Part of why it’s so hard is there’s so many factors. There’s so many variables. I see this clinically working on telehealth that I can almost predict someone’s chance of success with tinnitus based on a few factors. How long have they had it?

Hubert Lim, PhD.

Sure.

Ben Thompson, AuD.

That’s a big one. Do they have hearing loss? To what degree? That one is not so much of a variable. Are they dealing with a high amount of anxiety? Did they have preexisting high stress or high anxiety or insomnia before tinnitus? To what degree do they have insomnia with tinnitus? What kind of resources do they have? There’s all these factors that make it very complex to test this, I imagine. How do you control for those factors? And I would say the main one being there is a natural rate of improvement with tinnitus, especially in the first 18 months. How does one control for that natural habituation in a large-scale study like this?

Hubert Lim, PhD.

Yeah. Very good question. To answer your question, there’s two parts to that. There’s a lot of variability. So there’s one on the patient side. The other one is on clinical study design. So I’ll kind of break that up there. On the patient side, it’s challenging because it is a subjective condition and there’s a lot of other kinds of conditions that are linked to it. I won’t call them co-morbidity ’cause I don’t really like that word, but basically it means that there’s other aspects that can influence their tinnitus symptoms. If there are stress that they, like you said, if there’s some anxiety, if they’re just going through some tough times. They might even get sick and their body is feeling weak. All these things can play a role in modulating their tinnitus. At the stage, we don’t have enough objective measures of those things. There’s many groups out there, and really kudos to them because they are taking the hard problem of taking a lot of big data and trying to better subtype different types of tinnitus, and how we might be able to better characterize their progression, what treatments may be more effective for those different subtypes. And so I think we’re still just scratching the surface there. We have a lot to do and more funding is coming in that we can help identify that. And once we start to get more… They don’t all have to be objective, but if we get more, better metrics of classifying this, I do think then it’ll help us to assess which individuals belong in which group, kind of where, how treatment can happen and how we control or assess those compounding factors. So I’ll leave it at that for the clinical.

Ben Thompson, AuD.

Yeah. Yeah. Those questions of, will this work for somatic tinnitus, neck, jaw? Will this work for pulsatile tinnitus? Will this work for tinnitus in one ear? What about with hyperacusis?

Hubert Lim, PhD.

Totally.

Ben Thompson, AuD.

Basically you’re saying we’re not quite sure yet. There’s probably some,

Hubert Lim, PhD.

We’re not.

Ben Thompson, AuD.

some pathways, but we’re not quite sure.

Hubert Lim, PhD.

Yeah. Yeah. And there’s a lot to do there still. I want to give encouragement that there’s a lot of smart people. They’re smarter than me and more knowledgeable on tinnitus and demographics and characteristics and things. They’re working on that. And there are different groups that are formed around those topics. I do feel there’s a lot of encouraging opportunities there. On the second part–

Ben Thompson, AuD.

One of the strongest messages for us to share is a message of hope that even with tinnitus, you can live a happy, successful, by all means normal life. And that’s one of the main messages that is so needed to counteract the negativity online is a message of hope. Not to say this will be easy, not to say this will happen quickly, not to say that it won’t be at some times a struggle and you’ll feel potentially challenged or sad, or that you need some help. But longterm, this is something that can be well-managed. Another aspect of hope is, “Does anyone care about me? Or is there a scientific community? Are there researchers who are even trying to solve this problem? Or is this just being brushed to the side by doctors?” Well, you and your groups are showing, “Hey, we are looking into this.” It’s just a very tricky condition to solve. So yeah, now tell us, please, about the study, design and some considerations there.

Hubert Lim, PhD.

Yeah, yeah, and just to echo that, Dr. Rich Tyler always sends that same message to that. He’s the key person I’ve learned a lot from in the tinnitus field ever since I started, I went to a lot of his conferences, and just talking to him. But he says the same thing, right, just to really know that there are people out there that really do care about this problem, and that there’s ways to manage it and to get better. So I do resonate with that messaging. So thanks, Ben, for reiterating that. On the clinical study design, just stepping back there, a lot of what has been developed with clinical trial designs, what you’re going to see most of is what has come from the pharma world, the drug world. And I’m sure a lot of people are more familiar with it than they were before because of the vaccine trials, COVID pandemic. We’re always looking to see, oh, what studies are they’re doing? How did they track these and make sure they’re working? So I’m sure people have seen in the news. With drug trials, you’re going to have a treatment. And so that might be a pill, it might be a vaccine. And then you’re going to usually design it where you have a placebo control, right? And in the drug world, it might be a fake pill, or it may be just some fluid, but not the real vaccine. And you’re able then to, for the most part, blind individuals. I mean, the individuals who are getting sick more, or having side effects, they might realize that they’re in the treatment group, but they know what the side effects are, so there are some limitations. But overall speaking, you have this design. That’s the gold standard, right? I mean, that’s how it works. Now, moving to the device world, it’s been much more unique in a way, because you actually have a device. And if it’s a non-invasive device, people see the device, right. And so this has always been a challenge, for example, for the sound therapy world. Because, you know, you could say, “Here’s your sound therapy,” but then give them sound therapy with no sound. You can’t tell them that they’re not getting the no-sound treatment, and you can’t really blind it. So you can have a control and a sham that may not be blinded, right? And then you might have some challenges there. So there is some more creativity that has to go into designing those types of studies. But if you can come up with a creative design, then this is where you could show that one treatment modality is actually driving more improvements then a different condition. And that condition can be a control sham, or it could be also a low dosage condition. It doesn’t have to necessarily be a non-treatment condition. It could be a lower dosage treatment, or a different treatment. And then you would try to show a significant difference between those arms. So that’s kind of how you would go about to try to design a study.

Ben Thompson, AuD.

For devices that are either on the tongue, on the cheek, on the wrist, what are the considerations that we should have? My mentor taught me, “Hey, when we’re looking at different tinnitus research, different tinnitus treatments, few things, we want to scrutinize the research because there’s all these variabilities. And we also want to see a long-lasting effect, not something that just seems to work around six weeks. But then if we measure it at six months or 12 months, they’re back to where they started.”

Hubert Lim, PhD.

Sure.

Ben Thompson, AuD.

Thoughts on this and then gearing more towards what you guys have found at Neuromod Devices. Would love to get some updates there, too.

Hubert Lim, PhD.

Yeah. Yeah. And this is where, I’ll fuse that question together, because actually they go hand in hand. As some of your audience may know, we have this, for Neuromod Devices, we have this treatment, which is electrical tongue stimulation, and then also sound stimulation. And it’s combined together. And as I mentioned, bimodal stim to try to alter the awareness of the tinnitus to be suppressed. The sound, back, it came out in 2010 was the company and the device come out. So in Europe, at least, it was reasonably known what it was. In the US, I would say, after our publication, the last year and a half, we’ve got a lot more attention around it, and many more people know about it. And people do know it is sound stimulation, super threshold, so you can hear the sound, and it’s electrical stimulation of the tongue. You can feel it on your tongue, right? It is super threshold. So then you have to ask yourself, how do you design a study around this? And I’ve gotten many questions. People say, “Well, why don’t you just not do it with the tongue tip?” Or, “Why don’t you remove the sound stim, adjust to the tongue tip? But then you could imagine they’re going to know that they’re not getting–

Ben Thompson, AuD.

Why don’t you replace the tongue tip with a lollipop Would that work?

Hubert Lim, PhD.

We could, but I think your audience is smart enough that they would know that that’s not the real tongue tip. The situation there is, if we did the lollipop, if we did see a significant difference, then people would say, “Oh, people know they got a lollipop. It wasn’t the right flavor. It wasn’t the right sensation.” Whatever it could be, but they would know then, and they would argue that that difference was due to a placebo effect because they knew they didn’t get the tongue tip, and they knew they didn’t get the electrical stimulation. So you could see the inherent challenges there of designing something. Now, maybe if we did this in 2010 or 2012 before people knew about the treatment, then we can do what we do in the clinical world, which is you could… I mean, it’s ethical. You’re deceiving the subjects of what they’re getting, but that’s what they’re doing with the fake pill or the fake vaccine. But you could say that you are getting the treatment, but you just can’t feel it. Or you are getting this. You could do these types of scenarios and it could potentially work. But at this stage with so much super threshold stim and things like that. Now I will tell you where this brings us to Neuromod. What did we do? We thought about this very hard because it wasn’t an easy problem. We asked experts. And even when we did talk to experts, they would say, “Oh, you just use a sham control, just do this.” And then when we went into the details of this, they said, “Oh, geez, that’s harder than I thought,” in designing the study. So what we did in our studies, if you notice for the TENT-A1 and also TENT-A2. The protocol papers are out there, so you can read them on the link. If your audience wants to get the link, just have us email Lenire, or Neuromod, or myself. It’s all out there. What we did is a dose study. And actually dose studies are much more rigorous, in my opinion, than a placebo control sham because you never fully know if they’re blinded, because the problem with those is that they might notice something. It might be a side effect that’s different. There’s still challenges there. But a dose response, they are getting stimulation. It’s just a different pattern, right? And then you have your treatment, which is your optimal one. So to me, I think that’s the gold standard. And that’s what we did in our TENT-A1. We had three arms. They were all bimodal stimulation. They’re all blinded. The difference is, is that they can’t tell, obviously, ’cause they’re getting that super threshold stim, they’re getting the sound stim, but they’re different dosing, different patterns, right? And if you look at the three arms, the first one was our prime treatment.

The second one, we actually did it so that you couldn’t perceive at all, because we just altered some of the patterns, and we altered the delay, but the delay is not perceptually noticeable. So that was like, you know, we’re hoping that that could be an active control where you would see the difference. And there, that would have been the perfect, I mean, gold standard control, right, active control, ’cause they can’t perceive it at all. The third one was a different dose. At that time they don’t know. They might be able to, might argue that they can sense some difference, but since they don’t know what the first one is supposed to sound like, of course they don’t know what the third one is, right? That’s how we designed the study. Now in that study, which is published in “Science Translational Medicine,” we found that all three arms drove about, on average, 14 points improvement and tinnitus handicapped inventory. And so we saw significant improvements, double what people are claiming is the minimally clinically important difference, right, you know, clinically meaningful change of seven points. But we didn’t see a significant difference between those three arms, right? And this is where people have asked, “Well, we need to see a difference between those arms to know that it’s not just a placebo effect, or some other thing that happened.” But I will say to your other part of your question, we then saw that after we took the devices back, after 12 weeks, then the response, the sustaining effect lasted out to 12 months. Not in all, but in a large proportion of individuals, we saw that the effect lasted out to 12 months. And in fact, our number one stim was more sustained than the other arms.

Ben Thompson, AuD.

Got it, and so between those three groups, what did you find for the 12-month tail?

Hubert Lim, PhD.

Yeah. Good question. And so what we found was for that first group, it was sustained out to 12 months pretty flat, right? And then the second group, which was slightly different stim pattern than the first group, right, that started to go up a bit, right. And then the third one went up more in terms of going back to baseline, right. Now you have to be cautious here. We didn’t pre-specify. When you do a clinical trial, you have to say what it is you’re going to test. So that way you’re not cherry-picking the results. So I want to be cautious here. When we analyze the data, and these weren’t pre-specified, we actually saw a significant difference post hoc, so not pre-specified, but through post-analysis, significant difference between arm one and arm three. So that’s very encouraging because it means that, at least from an analysis post-hoc analysis, we’re starting to see a separation, and all three arms lasted out still significantly to 12 months.

Ben Thompson, AuD.

Thanks for sharing that update. And what do you see moving forward? We’re recording this at the end of 2021. So what do you see for 2022 and beyond in this field?

Hubert Lim, PhD.

Yeah, so, I think we’re just again scratching the surface here. So I’m a scientist and I know I am part of the company and there could be some views, biases, that I’m supporting, like Neuromod Devices. But I do want to make it clear that for me, I am a scientist and I’m looking at the data. And what has been encouraging for me is how many times by different independent groups, bimodal stimulation keeps showing effects. I’m not saying it’s perfect. All I’m saying is that my lab, I was working independent. Actually Neuromod, I viewed them as a competitor back in the day because they were the other group in Ireland. They don’t know what they’re doing. I know what I’m doing. So in my lab, I showed plasticity changes, real things happening in the animal brains. And then I did two pilot studies, and we had encouraging results, and some of that was talked about in “Tinnitus Talk.” Dr. Susan Shore, she was independently doing bimodal stim, different things, but then you’ve seen her work published in “Science Translational Medicine” as well, how encouraging it was to see in the animals, these changes happening, but also in a pilot human study she did. And then Neuromod in Ireland was doing their stuff. I had nothing to do with them.

So 2017, they were showing consistent results. So then you have to ask yourself three different groups, right? And I would say even other groups who are doing vagus nerve stim with sound, that’s bimodal stimulation, they were showing that you can alter tinnitus effects. So all of this together to me means that there’s something here exciting. Now the challenge with neuromodulation is how do you optimize it per patient? And I think that’s where I’m really excited as a scientist is how do we try to figure out, back to your original question, the different subtypes that you have, the different characteristics of their tinnitus, and how do you then alter or optimize the stimulation bimodal to make it even more effective for each individual? And I think that’s the future, right? In our group with Neuromod Devices, we’re going to take what we have and try to get it, it’s in Europe, get it to the US at some point through the FDA process. But once that happens, the idea is how do we optimize it for each individual?

Ben Thompson, AuD.

Absolutely, and on top of that, how do the clinicians counsel and understand all of this complexity to make simple recommendations and create realistic expectations for our patients? That’s the golden question that as a collective community, we’re going to get better and better at over time. So for the audience here, try not to get overwhelmed. Don’t have FOMO, fear of missing out. “Oh, I have to try this right now.” Maybe not quite yet. Maybe you can in the future. Maybe you won’t need it. Just remember it is out there and there are professionals who can counsel you based on your individual case, because what has come up over and over is that tinnitus is an individual management. It’s not something that can be a one-size-fits-all solution. And there’s a lot of intricate details that need to be worked out. There’s also many other resources to manage tinnitus other than bimodal stimulation. And the way I’ve been approaching this counseling patients is, “Let’s focus on the fundamentals first and consider other resources when the time is right.” Dr. Lim, I want to thank you so much and your scientific community for working in this space, and I’ll give you the last words here. Do you have any final messages, ways that people can stay up to date on this research, and any last message here for those with tinnitus?

Hubert Lim, PhD.

I wanted to echo, and you said it very well, just that there’s different individuals, there’s multiple opportunities and options for them, and not to rush into any one thing because of the urgency. That is a key valuable message. Thank you for sharing that, Ben. From my side, we are just one option, and just to echo what you said, and people who are interested in bimodal neuromodulation, there are different groups that are interested. As you know, Dr. Susan Shore is also working on that, Neuromod Devices in Dublin. And if you’re interested in more information, obviously you can scroll through Neuromod Devices on Google and look up their website to get information. I let them handle things that are going on on that side. I’m more focused on the research and scientific side of running clinical trials. But if you’re interested, you can go over there. In terms of optimistic hope side that you brought up, Ben, there are many more people who are really taking attention to tinnitus and hyperacusis as well. And there is an understanding that this is a major health situation. Funding is coming in, and so we are working hard to push more solutions for everyone. So I just want people to know that it is changing. There is more momentum. It’s an exciting and encouraging time.

Ben Thompson, AuD.

Thank you so much, this is Dr. Hubert Lim from University of Minnesota, professor of biomedical engineering and otolaryngology. You’ve been a wonderful guest. We’d love to have you back some time. My name is Dr. Ben Thompson, audiologist. Thanks for watching this episode. Make sure to check out the other episodes on my YouTube channel to learn some important details about tinnitus and how you can manage it. Take care, everyone, bye bye.

**Update: As of March 7th, 2023, Neuromod’s Lenire device has been granted FDA approval for bimodal stimulation, and can now be used by tinnitus patients in the United States.