Jasmin Pfeifer: Studying congenital amusia - hereditary tone-deafness

Jasmin Pfeifer, Image courtesy of Jasmin Pfeifer

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Kat: As we heard from Reyna, music is closely linked to language in our brains. But although there isn’t a specific music gene, at least to some extent, musical ability is in our genes. But what about the opposite? What about the small number of people who genuinely can’t seem to perceive music at all? 

Jasmin Pfeifer, from Heinrich-Heine University in Dusseldorf, Germany,  is a linguist by training, who’s found herself involved in the world of genetics through her studies of a condition called congenital amusia, or hereditary tone-deafness. So, what is amusia?

Jasmin: Well, the scientific description would be it's a neural-developmental disorder that affects music and speech perception in a negative way. To present it in a more accessible way I'd say it's a disorder that negatively affects how people perceive language and music. So for example, amusics cannot say whether two songs are different if you take away the lyrics. So if you play them Happy Birthday and you take away the lyrics, they wouldn't be able to tell you that it's Happy Birthday. Or if you play two piano tones, they can't tell those tones apart. Or if you ask them to clap along to a rhythm, they can't clap along.

Kat: So is this when people say, oh, I'm tone deaf, I can't sing in tune. I can't hold a tune. Is that the same thing? Or is there something more serious?

Jasmin: Yes and no. So it is definitely more serious, but this is how we find the people actually. So all the amusics will say about themselves, oh, I'm tone deaf and I can't do all of that. But not all of the people who say that are actually amusic. So roughly 15% of the population are said to be or would characterise themselves as not musical and say they can't sing in tune for example, but only about 1.5 to 2% of the population are actually amusic.

Kat: And so how are you trying to study this condition? Because as a geneticist, I'm intrigued about, is this something that runs in our genes? Is this something that is in the environment? So how are you trying to figure out where does this amusia come from?

Jasmin: So, as I said before, I'm a linguist. So my starting point was probably different from what yours would have been. I've been doing a lot of behavioural studies to start out with, so to really map the phenotype of the amusic. In the beginning when I started looking at this disorder 10 years ago, we really weren't sure whether language is even affected by this disorder. So this is something that I was really interested in.

Jasmin: So I started looking at the language impairments that amusica might have and found quite a few, language impairments is a strong word here, but they do have trouble with specific aspects of language perception. So they have trouble perceiving intionation. So telling a statement from a question when the sentences are exactly alike, they have trouble with that. And then there's also trouble with certain vowels where they can't perceive a difference. And we've been going at it from this angle to start.

Kat: So how did that draw you then to music from this kind of tonal aspect of language?

Jasmin: So I started being more interested in what was really going on in their brains and then also in their genes basically. So we started doing EEG studies and TACS studies to really figure out what was going on in their brains.

Kat: So what's a TACS study? How does that work?

Jasmin: It's one of my favourite studies actually that we've done so far, it's electric brain stimulation. So there's magnetic brain stimulation that you can do and there's electric brain stimulation. So we basically introduced a current to their brain that a previous study had been found that was missing. We introduced that and tested whether that would make amusics a little bit better at a certain aspect, so basically a tonal memory, and we actually achieved that. So we could show that this specific current was missing in and specific brain area and by introducing that to their brain we actually made their tonal memory little bit better perception.

Kat: Wow. So you slightly zap someone's brain and then they're better at hearing music. That's wild!

Jasmin: Yes it is. So they weren't actually better just their memory was better because it was that specific aspect that we focused on. But yeah, basically it's absolutely wild.

Kat: That's absolutely incredible. So let's dig into the genetic side a bit. So why do we think that there might be a genetic component to this? What gives us those clues?

Jasmin: So there was a first study in 2007 by Isabelle Peretz and her group in Canada. She's really the pioneer in this field. And she did a family aggregation study in 2007. So she had nine large families with 23 amusic individuals, and she drew family trees and did a so-called family aggregation. So she calculated a risk that amusic's siblings would also have amusia. And from there on out people kind of thought that it was a hereditary disorder, but no-one's really looked into it further since then.

Kat: So I know that one of the ways that we study the inheritance or try and dissect how much is genes and how much is environment is through studying twins. So that's what I have to ask is, has anyone looked at twins? Whether this stuff is the same between identical twins or different?

Jasmin: So, yes, actually, we're very lucky. We just happened to come across one dizygotic twin pair. So we actually did a study on that. We were the first one and only case study, I have to say, but it's still interesting. I think.

Kat: So these are non-identical twins. These are basically like kind of brother and sister, but born at the same time effectively.

Jasmin: Yes, exactly. And we figured that would be a really nice example because they share roughly 50% of their genes, but they grew up in exactly the same environments. So the twin pair that we had, they were female 27 years old at the time of testing and they grew up together under exactly the same circumstances. They went to school together, they went to kindergarten together, to school together, to high school together and they even went to university for their undergrad degree in the same subject together. So their upbringing is as similar as possible basically.

Kat: And what about their amusia or musia? How does that go between them?

Jasmin: So, yeah, that was the interesting part because one of the twins was actually amusic and the other twin wasn't amusic. So that was why it was so fascinating for us. They had the same upbringing, they had 50% of the same genes, one had the disorder and the other one didn't have the disorder. So we figured this is perfect for trying to tease apart what was going on. And, well, that's what we did. We applied a huge battery of tests. We had them in the lab for several weeks, I think, and did a whole test battery with them to see what was going on.

Kat: That's absolutely fascinating. So what did you find when you started to look at them? What's come out of that?

Jasmin: Well, so first we looked at their musical aptitude, we looked at their language aptitude, and we looked at also their spatial perception because there were a few studies claiming that there was something going on with amusia and spatial perception as well. There was one study that found that spatial perception was somehow affected by amusia. And two other studies that found that nothing was going on there, but we figured we'd include it nonetheless, just to see what was going on.

Jasmin: So we showed that the twins actually had an identical, low pitch memory span, which was really fascinating because for the non-amusic twin, you'd expect a higher pitch memory span. So pitch memory span basically means you play a couple of tones and you repeat them and they have to say whether they were the same or not. And then you calculate a span of how many tunes they can retain in their memory and you would expect the non-amusic twin to have a fairly high span, but she didn't. So here was actually interesting again, because pitch perception has been shown to have a certain hereditary component by a study in the early 2000s. So now we also wondered wether pitch memory would also be affected by this hereditary component.

Kat: So that's really interesting because that says there's kind of different components to this isn't there? There's whether you're perceiving the pitch of a note, whether it's high or low, and then also how you can remember a tune and how long a tune you can remember. So that suggests that this is going to be quite complicated, maybe at a genetic level.

Jasmin: Yes. Definitely, definitely. It kind of hints at that, this is like multi causal or polygenic basically. So that's the thing here. It's most likely that not only one gene is causing amusia, which would be like a nice, simple solution saying, oh, this is like this gene, and then you have amusia, but that's most likely not what's going on. So it's most likely different genes that somehow are affected or affect one another and it's kind of complicated. I think.

Kat: I mean, it's always lovely to go, oh, it's the tone-deaf gene. And you've either got it. Or you haven't, but, yeah genetics is often more complicated, isn't it?

Jasmin: Yeah. The thing is, so there was one study that's not actually published yet, but I listened to it at a conference. So again, Isabelle Peretz looked at FOXP2, which is sometimes referred to as the language gene. And she was interested in whether that might be causing amusia. So she tested a large cohort of amusics, but she actually found that this is not related to amusia at all. So at least we conclude that this has nothing to do with amusia, but now the question is still open.

Jasmin: What is the genetic underpinning? Is there one brand what is actually going on? So I don't have an answer to that yet, but we managed to identify a large family that has four generations, and we have one amusic in each generation, which is really nice. And we actually took their DNA samples and are analysing them right now, or actually we were analysing them. But then our DNA got shipped off to Wuhan last year.

Kat: Oh no!

Jasmin: And, uh, yeah so it got slightly delayed, the study, but hopefully we'll have the results very soon and I might be able to answer this question in the near future, whether we can at least make an educated guess about what is going on based on this first family that we're looking at.

Kat: Oh my goodness. That is a COVID problem that I never expected! Because obviously they have huge sequencing facilities in China and accidentally sending your samples to the epicenter of a pandemic.

Jasmin: Yeah, It was great!

Kat: Oh no, I'm so sorry. So when you get the answers back, that should be really fascinating because you've got, I guess if you've got generations and then you've got some affected and some not affected that should really help you to piece this together.

Jasmin: I hope so. I really, really hope so. Well, we were thinking about different approaches about how to best do that. We could also have done a genome wide association study, which is what we thought about first, but it would need such a large cohort of amusics that it's really not feasible. I mean, I have a pool of about 50 amusics, which I've recruited over the last 10 years, but that is obviously nowhere near or close enough to a big number that I would need for GWAS study. So we figured how else could we approach this? And then we were really happy to find this family.

Kat: I'm really intrigued finally about the kind of cultural side of this, because there are some languages like Mandarin that are very, very tonal and, you know, the same words just in the intonation can mean two very different things.

Jasmin: Yeah.

Kat: So the source of a lot of misunderstanding in some cases. So is there any evidence that this connection between music and speech and language might be different in different countries or that people with these kinds of problems of amusia or hearing musical tones might struggle with some languages more than others?

Jasmin: That's actually an excellent thought that, for the longest time people thought there would be no such thing as amusia in tonal languages because those people would have to be severely speech impaired, right. But as it turns out, there also seemed to be roughly about 2% of amusics in tonal languages.

Jasmin: They looked at Mandarin and Cantonese and some other tonal languages, and there are just as many amusics, but the puzzling thing is in everyday life, they seem to be doing absolutely fine. So they have no trouble telling the tones apart in everyday speech. But then again, when you take them to lab and you take away the context and they only have the tone, they struggle and they have difficulties. So that again, shows that language utilises so many different cues. So we not only have tone or intonation, but we also have facial expression, we have context, we have gestures. So amusics most likely also rely on those other cues, more strongly than other people that's helped them in everyday situations to communicate normally.

Jasmin: So even in our languages, German or English or whatever language you speak, you wouldn't be able to tell that you're talking to an amusic because some people think they will have a very flat intonation for example, but they don't.

Kat: I do find it incredible, and the more that I learn about the brain and the genetics and all the influences and everything that's coming in that we're processing and trying to make sense of the world, it's an incredible thing that the human brain does to just take all this stuff and make sense of it for us.

Jasmin: Absolutely. And I mean, it is so fascinating to see how like the different puzzle pieces can come together and how our brain makes sense of various information or then sometimes fails to do so in case of amusia, when you take away other cues,

Kat: I mean, one story that I always like to tell is about one lady that actually came to me in the lab and she just started crying because she was so desperate. Apparently one thing where context didn't help her, is her boyfriend or husband at the time was using irony a lot and irony strongly depends on intonation. And she never could tell when he meant something in an ironic way and apparently led to so many arguments that they finally broke up because she just was never able to tell when he meant something and when he didn't mean it and he just couldn't grasp why she wasn't able to.

Kat: Oh no! So yeah, I guess this stuff without the right context, it can really be a problem. Yeah,

Jasmin: Definitely. And she was so desperate. I mean, at least I was in a small way able to help her by explaining to her what was actually going on with her perception, because she basically just thought she was going crazy because she just couldn't make sense of it and everyone else could. 

Kat: I guess that’s one way to get rid of an annoyingly sarcastic boyfriend.  That’s all for now. Thanks to my fascinating guests, Jasmin Pfeifer, and also Reyna Gordon.