OHSU researchers connect tinnitus with elevated serotonin activity in the brain

It’s estimated that 1 in 10 adults experience tinnitus, often described as a phantom ringing noise in the ears. The condition can develop due to head trauma, hearing loss, exposure to loud noise or as a side effect of certain medications.

There’s no cure for tinnitus and its origins have long been a mystery. But new research from Oregon Health & Science University has linked tinnitus with elevated serotonin levels in certain regions of the brain. While far from a cure, the discovery could one day help scientists understand how to reverse the condition through brain chemistry.

Larry Trussell is a professor of otolaryngology at OHSU and interim director of the Oregon Hearing Research Center. Angie Garinis is an associate professor of otolaryngology at OHSU and a member of the Oregon Hearing Research Center. She’s also a principal investigator at the National Center for Rehabilitative Auditory Research at the Portland VA.

They both join us to talk about what this new information could mean for patients who suffer from tinnitus.

Note: The following transcript was transcribed digitally and validated for accuracy, readability and formatting by an OPB volunteer.

Dave Miller: From the Gert Boyle Studio at OPB, this is Think Out Loud. I’m Dave Miller. An estimated 1 in 10 adults experience tinnitus. It’s often described as a phantom ringing noise in the ears, but that doesn’t really capture just how disruptive the condition can be or how much it can diminish one’s quality of life. There’s no cure for tinnitus and its origins have long been a mystery. But new research from Oregon Health and Science University has linked the condition with elevated serotonin levels in certain regions of the brain. And the hope is that one day this discovery could help lead scientists to a clinical breakthrough.

Larry Trussell was one of the senior authors of the new study. He is a professor of otolaryngology at OHSU and the interim director of the Oregon Hearing Research Center. Angie Garinis is also at that center. She’s a clinical audiologist and associate professor of otolaryngology at OHSU. She’s also a scientist at the National Center for Rehabilitative Auditory Research at the Portland VA. They both join us now. It’s great to have both of you on Think Out Loud.

Larry Trussell: Good to be here.

Angie Garinis: Thank you so much.

Miller: I want to start with a voicemail that we got. It’s a little bit long, but it really gives those of us who have not experienced tinnitus a good overview of what it’s like. This came in yesterday from one of our listeners, Adrian, in Portland. She says she’s had tinnitus for the last 11 years.

Adrian [voicemail]: It was caused by earbuds. My ears are sensitive to loud noises. For instance, if silverwares dropped, that’s painful to my ears now. It disrupts sleep. It disrupts meditation. For me, the quieter it is, the worse the tinnitus is, because that’s all you hear. And it’s like a screaming in your ears for me. It’s high pitched, nonstop. There are times where it’ll suddenly increase for minutes to hours or days, and I’m always concerned that that increase becomes permanent. It’s not a static condition. It worsens. It’s a horrible affliction, and quite honestly, I would never wish it on my worst enemy.

And because it shows no physical signs of disability, it’s a silent torture. It’s something that, unless another person you’re speaking with is afflicted with it, they simply can’t comprehend living with it. It’s sometimes indescribable. And I wish there was something that would help it permanently. I will say I do notice things that will increase it, like food allergies, stress, but nonetheless, the underlying constant screaming in my ears is nonstop. I will add that the only way I’ve survived this is I’ve basically mentally accepted it, but that took me about two years.

Miller: Adrian, thank you for that call. Larry, how do you describe tinnitus?

Trussell: Well, there’s different types of tinnitus. There’s tinnitus that is originating within the ear, but the majority of it seems to be tinnitus that originates within the brain, central tinnitus.

Miller: Can you help us understand that? So we’re talking about a sound that is not originating in the ears, not originating outside a body, some vibration that’s picked up in the eardrum, and then made sense of in the brain. You’re saying it starts in the brain.

Trussell: Yeah, it takes up residency, we could say, in the brain. One of the major theories is that it reflects a hyper-electrical activity and ongoing firing of electrical signals within specific parts of the brain that is constant. So with regards to Adrian, I can commiserate because I also experience tinnitus, which is constant high pitched in my case, in her case, a constant high-pitched sound – and it’s unrelenting.

Miller: Given that this is the perception of a sound that nobody else can hear … there’s a question of is my red the same as your red? There are sort of perception questions that humans may ask late night, but there are objective things that are happening out in the world that we agree on. This is different. This is an objective thing that’s happening inside your own head. How can somebody else really know what a person is experiencing?

Trussell: Well, we have language, right? So we can talk to each other. Adrian, for example, communicated what it sounded like. I can mimic my tinnitus actually just by producing, say with a sound generator, a high-pitched sound. Mine is roughly the sound, the pitch you’d get if you reached over on a piano keyboard and hit the farthest key to the right. That’s a little over 4 kilohertz. That’s a very high-pitched sound. If you can imagine that sound continuously, that’s a way to communicate what is a subjective experience.

Miller: Angie, with what Larry’s talking about there, and Adrian and other folks – and we’ll hear other voicemails over the course of this conversation – almost everybody is talking about high-pitched sounds. Are there theories as to why, as opposed to middle range or bass notes?

Garinis: Yeah, that could be more of a mechanism question for Larry, but in terms of a clinical interpretation, I would say the highest pitch, those high-pitched tones, are the most commonly reported. But others might report clicking, they might report buzzing. Sometimes patients will come in, and they say their tinnitus changes throughout the day. It’s highly, highly variable. Just briefly, going back to Adrian, I will say that most people who come in for help because of tinnitus, it’s due to the quality-of-life impacts.

Miller: I want to hear more about that, but let’s listen to another voicemail. This is from Carolyn in Springfield … and just a heads up, she does talk here about domestic violence.

Carolyn [voicemail]: I’ve had it for a number of years, going on four decades now, and it was originally from a domestic violence situation. I was hit repeatedly in the head during a decade-long marriage and the only way to actually fix it would be to do surgery, which may make it worse or make it better. And since it’s a 50/50 chance and I’m used to it, I just kind of deal with it. But the one thing I will say about it is when you’re really trying to just have quiet, the more quiet it is, the louder it is in your head. It’s like someone loosed an angry swarm of bees inside your skull.

Miller: So our first caller there talked about getting tinnitus from earbuds. Carolyn there is talking about physical trauma, blows to her head. What are the various potential causes of tinnitus?

Garinis: So, we know clinically, patients will come in and the most common is that it’s highly associated with hearing loss. The first thing we always say is if you report any type of tinnitus, get your hearing tested and see, do you have hearing loss associated with the ear, where you’re hearing the tinnitus first. Second is noise exposure. We know this even from veterans that are highly exposed to noise, that there’s also a high compensation rate for tinnitus because it’s the number one disability at the VA. Third would be traumatic brain injury or concussion. Similar to this last caller, any type of impact can cause some type of neural damage that patients will report some type of tinnitus with a different quality. It’s not always the high pitch. It could vary.

When it comes to exacerbating or changing your tinnitus, that could be the lifestyle factors. So caffeine, whether or not you smoke, whether or not you drink alcohol, lack of sleep can either increase or exacerbate your tinnitus, or you can improve it by trying to improve your lifestyle factors.

Miller: Larry, you mentioned that you can commiserate because you experience tinnitus yourself. How has it impacted you?

Trussell: Well, first and foremost, it’s gotten me really interested in tinnitus.

Miller: So you’re partly a researcher into this because you have the condition yourself? The condition came first for you before the research?

Trussell: That’s true, and when you have a condition, you can empathize with others much more readily. So in a way, you could say that tinnitus has been a gift to me because now I have a way to relate to this patient population and it made it one of my missions in my research career.

Miller: What are the challenges of researching tinnitus?

Trussell: Tinnitus, in a way, is a big mystery because it’s a subjective sound. So, as a neuroscientist, we’re interested in the neural basis of mental activity. We would say the question is, what neurons in the brain are hyperactive, if you will, and what is making them hyperactive? So, those are the two questions we want to ask. Well, the brain is a big organ, so where is this originating? And there’s a lot of theories about it. We ascribe to the idea that it’s beginning right at the beginning phases of auditory processing in the brain stem and others believe that it’s happening at higher levels, like in the cortex. So trying to understand where it originates and what the neural basis of it is our mission.

Miller: I want to play another voicemail because this gets to, in a roundabout way, some of the research challenges. This is Dylan from Bend.

Dylan [voicemail]: I’ve had tinnitus since childhood. I have like a really clear early childhood memory around age 6 or 7, trying to describe this ringing, the constant, constant ringing that I couldn’t get rid of. They thought it was a dishwasher or something, but I guess I just probably didn’t have the vocabulary to describe it very well.

Miller: Angie, you treat adults and kids with tinnitus, I understand. What are the challenges of helping kids?

Garinis: As adults, I think, we have the language and the understanding of how to describe it to make it more relatable to someone else, but a child really doesn’t understand what they’re hearing or what they’re experiencing. Many times, they might think it’s normal if they’ve had it for a very long time and they might describe it like something in their environment, like “I’m hearing crickets all the time.”

I always loved telling the story about a parent that came in and had brought the child in the booth, and said, “I’m really worried that my child has schizophrenia because they’re hearing a symphony in their head all the time.” So the child knew how to explain their tinnitus like music, and so they would relate it back to that. And it wasn’t schizophrenia or a psychiatric issue. It was really, they had ringing in their ears.

So the challenge is, one, being able to understand and really relate to that child, to be able to experience and to explain what their tinnitus sounds like and how they can relate it to their environment. And once you have that, then you can talk about what are some strategies to help them manage and cope with it.

Miller: Larry, I wanted to hear that voicemail from Dylan because you use animal models. Where at least you can talk to parents and kids and help them develop a vocabulary. You can’t do that with a mouse. So how do you build a helpful animal model in mice or other animals to research tinnitus?

Trussell: This is a really important question, because we can use animal models to probe mechanisms, brain mechanisms, of different diseases, but when you’re dealing with a subjective experience, the only way you can do this kind of work is to try to develop a model in which the animal acts as though it is hearing a sound. So you have to devise behavioral tests that were, in our case, in which the animal is initially trained to hear a gap in a sound.

Miller: So there’s a sound, and then it stops, and then it starts up again?

Trussell: Exactly. And then the animal is trained to respond in a certain way when it hears the gap. And then if you do some manipulation that we believe could induce tinnitus, and the animal then acts as though it’s not hearing that gap, that is our best effort at saying, well, the animal is hearing something that is not present in the room, so we’ll call that tinnitus.

Miller: OK. That is, they’re not reacting in a way that they’ve been trained to react. They’re not hearing silence the way their mousy peers are hearing it. It seems like there’s some kind of constant sound and that is the best way you’ve been able to engineer, to mimic, their experience of tinnitus.

Trussell: And we can actually determine what frequency that sound is. We can test gaps of different sound frequencies. We can say the animal seems to be hearing a sound of a certain frequency by how it’s behaving.

Miller: When did you start looking into serotonin and why?

Trussell: About 10 years ago we began working on this. It started because we noticed that patients who were taking SSRIs – some of them, not all of them – would report an enhanced ringing of the ears.

Miller: These are a class of antidepressants like Prozac, Zoloft and others. Selective serotonin reuptake inhibitors.

Trussell: Exactly.

Miller: OK.

Trussell: And so we thought, well, if tinnitus has a basis in the brain, why are these drugs that should be producing relief from depression or relief from anxiety, why is it doing something that seems to be elevating an anxiety-promoting experience? Patients were certainly complaining about it. So we thought, well, let’s just see what serotonin does to these neurons in the brain that are thought to be important in tinnitus.

Miller: What earlier research had you done to try to unpack the potential connection between serotonin and tinnitus?

Trussell: What we initially did was simply to develop an experimental model in which we could make electrical recordings from the neurons that had been proposed to be involved in tinnitus, and then apply serotonin to them and see what happens. What we found is that serotonin was highly excitatory to them.

Miller: In this particular place it’s connected, it seemed, or you know, to auditory sensation?

Trussell: Yes, absolutely. So when they’re exposed to serotonin, their activity increases. We thought, well, this is interesting that if serotonin’s elevated, maybe there’s an enhanced percept of tinnitus for these animals. And we also, at that time, worked out exactly why that’s happening at a molecular level.

Miller: So Larry, that was the earlier research. What did you do in the latest study that is the reason for this conversation today?

Trussell: Yes, well, that initial study said serotonin could be important. Now, let’s find out several things. Number one, is serotonin actually produced by the animal, in this case a mouse, and secreted or released into this auditory region? We found that it was. And if we activate those serotonin releasing pathways, could that induce in the animal a condition that resembled tinnitus? And it did. As though just releasing the serotonin into this auditory pathway could induce tinnitus.

Miller: So, what’s the significance of this? I mean, you’re a researcher who, I imagine, you’re excited about your research and you would like to see this as significant. But if you sort of do your best to step aside and look at the 30,000-foot view of the world of tinnitus research – and then we’ll talk about the clinical side too, Angie, in just a second – how do you think about the significance of this finding?

Trussell: First of all, it fits together a lot of puzzle pieces in my mind. It says that these brain chemicals, neuromodulators like serotonin, play a role in this process. That has clinical implications, but it also gives us a new handle that we didn’t have before on how to study tinnitus. Are these neuromodulator pathways like serotonin and others like norepinephrine, are they not only enhancing tinnitus, maybe they’re causing it? This is a new research direction that, from my 30,000-foot level, I’m very excited about.

Miller: Is this the kind of paper finding that changes what other researchers are doing? I guess I’m wondering if there are other researchers who have been excited about other models, have had other theories about the way tinnitus works, and then they see this work of yours and the previous one they say, you know what, I guess I’ll start looking into what Larry’s doing.

Trussell: I sure hope they do. [Laughter]

Miller: So let’s turn to the clinical side here, Angie; what went through your mind when you started to really understand the findings that Larry is talking about?

Garinis: As a clinician, everything that we do is really based on evidence-based research, so understanding mechanism really helps with the way that we end up tailoring our therapeutic approaches for patients depending on the condition. Initially, my thought was … I also do research in ototoxic therapy, so Larry’s presenting new data that might support a potential mechanism for tinnitus.

My recommendation to patients wouldn’t necessarily change in terms of how we deal with tinnitus, except that I would say, absolutely talk to your physician if you have concerns with your medication. If you’re on an SSRI and you have a concern about also having tinnitus, you need to weigh your therapeutic benefit with what your side effects are.

Miller: The way you probably are hopefully doing if you’re taking any medication. Every medication has some kind of side effect, but this new finding may then suggest a new set of questions that doctors should be having with their patients.

Garinis: Absolutely. And I’d also say every medication that you take will say potential side effects. So not everyone’s going to be impacted by it. There may be plenty of patients on SSRIs who don’t develop tinnitus or don’t have it, so it’s important to note that this is more information that really points towards mechanism. But in terms of clinical practice, I would say, for someone, regardless of the medication you’re on, if you have ringing in your ears, it’s a quality-of-life impact. Approach an audiologist, get your hearing tested first. And then what we typically do about that is it’s important to maybe combine, collaborate with a behavioral therapist to work on improving your quality of life by reducing the impact on your life, your coping skills with it.

Miller: Let’s listen to another voicemail. This is Leslie from Sisters.

Leslie [voicemail]: I’ve suffered from tinnitus for many years, and it’s like screaming high tones, like cicadas 24/7 with no relief. But I try to distract my brain from its own noise by always having outside sound to focus on. I listen to OPB every day, all day. It has saved me. I listen to soft water sounds at night, but don’t get a lot of sleep.

I’ve read a lot of posts on Facebook support groups for encouragement, and I have some serious concerns because a lot of the posts make me believe that there’s a very high suicide rate among people with tinnitus or a high rate of suicide ideation, at least. I just thank you for addressing this issue. There’s many sufferers who never speak about tinnitus because it just seems hopeless and people don’t understand. Thanks so much.

Miller: Angie, can you give us a range for how tinnitus affects your patient’s quality of life?

Garinis: So this voicemail, basically her report is really common, and I would say that you have plenty of individuals that come in that have it. They can describe it as high pitched, moderately loud, and they can ignore it. And then you have the other range where people have what they consider to be a low-pitch tinnitus, maybe clicking, sometimes moderate volume, and it’s impacting every aspect of their life. They don’t go to noisy concerts. They don’t go to restaurants, so they have huge quality-of-life impacts.

Miller: We got another voicemail that I’m not going to play now, that talked about the hit to socializing because of what you’re just talking about, not going to restaurants, not going to concerts, not hanging out with friends the way they used to because, often, that socializing would be in places where they feel like they can’t exist there right now.

Garinis: Absolutely. But I think what Leslie said is that there’s something you can do about it. There are approaches. And the first thing is to get your hearing tested because we know that individuals who have hearing loss, who also have ringing, may have benefit from hearing aids. So that can help mask the ringing. And then also, the natural, “I listen to white noise,” or “I listen to ocean sounds,” or “OPB’s is a therapeutic masker for tinnitus.” Every individual…

Miller: That’s our new tagline: therapeutic masker for tinnitus. We’ll take away, we’ll distract you from the never-ending ringing in your ears. [Laughter]

Garinis: Right. So, we have to remember that it is subjective in the sense that I can take two people, play a sound like Larry recommended at the same volume, and one might say that it’s excruciating, the other individuals say that it doesn’t bother them. We have to work with our patients in a very patient-centered way to be able to help them with the coping aspect of it. You can do that with sound therapy. You can do that if they need hearing aids. But there are approaches to help. So patients should not suffer in silence.

Miller: Larry, what are you excited to research next?

Trussell: Well, the language that I’m hearing now is that tinnitus might be a side effect of these medications, and that raises an interesting point because what is a side effect? Disease fundamentally has some physiological and molecular basis. And drug actions, treatments for diseases, has a molecular basis, and side effects have a molecular basis. So if we stop treating things as just like, “oh, it’s off there in the corner, it’s a side effect,” but instead look at it as something that we can learn from – what is the basis of this effect of this drug in this region, as opposed to the region that might be associated with the disease – we can start to pick apart why these so-called side effects are happening, and then target treatments that avoid those pathways and focus on the ones that people really care about.

Miller: Larry Trussell and Angie Garinis, thanks so much.

Trussell: Thank you.

Garinis: Thank you for having us.

Miller: Larry Trussell is one of the senior authors of a new study looking into the connections between serotonin and tinnitus. He’s a professor of otolaryngology at OHSU and the interim director of the Organ Hearing Research Center. Angie Garinis is also at that center. She’s a clinical audiologist and an associate professor of otolaryngology at OHSU. She is also a scientist at the National Center for Rehabilitative Auditory Research at the Portland VA.

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