How a spinal device could relieve a neglected effect of cord injury

Host: Shamini Bundell

Welcome back to the Nature Podcast. This week, a prosthetic to treat blood-pressure problems caused by spinal injuries.

Host: Nick Howe

And the neurons that help us understand other people. I’m Nick Howe.

Host: Shamini Bundell

And I’m Shamini Bundell.

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Host: Shamini Bundell

The first thing that comes to mind when we think about spinal-cord injuries is paralysis, but there are lots of other ways that people can be impacted. One that’s particularly overlooked is blood-pressure instability. Let me give you an example. Imagine you’re lying down, you hear the doorbell ring and suddenly you jump up only to be met by a wave of light-headedness, maybe you even faint. This is caused by your body being a bit slow to react and not increasing your blood pressure fast enough to compensate for your movements. For most people this is an occasional annoyance, but for those with spinal-cord injuries it can be constant and debilitating. That’s because the system responsible for monitoring and maintaining blood pressure – the so-called baroreflex – can be damaged as a result of these injuries. Now, a team led by Grégoire Courtine from the Swiss Federal Institute of Technology have come up with a novel solution – a neuroprosthetic system which aims to monitor and maintain blood pressure for spinal cord injury patients. They’re calling it a synthetic baroreflex. Noah Baker gave Grégoire a call and started by asking him a bit more about the natural baroreflex.

Interviewee: Grégoire Courtine

The natural baroreflex measures the blood pressure. It’s conveyed to specific cells, neurons, that are located in our brain stem, and then when these neurons detect that the blood pressure is too low, they will activate what is called a sympathetic circuit that are located through the spinal cord in order to increase the vital constriction of blood vessels. That’s what increases the blood pressure.

Interviewer: Noah Baker

And that’s very much what you have been working on here, is trying to design a prosthetic device that could help create this baroreflex in those that have lost some of that function due to spinal cord injury. Tell me about the device you’ve been working on.

Interviewee: Grégoire Courtine

We have an electrode array, so you imagine like a second skin that slides on top of the spinal cord, and the electrodes are very precisely located in order to target the neural circuits that normally regulate blood pressure. And then we have a catheter in the artery that measures the blood pressure constantly in real-time and detects the needs for the blood-pressure modulation. So, these go through a computer, a mini computer, very smart, located in the abdomen, that will deliver electrical stimulation to the spinal cord. And what is very novel here is that the stimulation of the spinal cord, they are so-called biomimetics, in the sense that they reproduce the way the brain stem, our brain, would naturally activate the spinal cord in order to modulate blood pressure.

Interviewer: Noah Baker

You said that your prosthetic is very specifically targeted towards the neurons that work in the system, but trying to work out which neurons those needed to be is actually a whole process in itself. To some extent, that was a bit of a trial and error procedure to get to that point.

Interviewee: Grégoire Courtine

Yes, it’s very difficult, of course, to dissect the specific neurons that are first involved in blood-pressure instability and then second that we are stimulating with our neural prosthetic system. People tend to see the spinal cord as one tube with reflexes and simple circuits, but the spinal cord is a brain in itself, and a lot of functions are distributed throughout the spinal cord. But we are living in an extraordinary time for neuroscience because we have such precise tools to dissect the neurons, the connections. We have been able really to identify a very small region in the middle of the back that has a high concentration of these circuits. We call it the haemodynamic hotspots because when we target this specific region, we have an incredibly higher level of efficacy in the modulation of the blood pressure.

Interviewer: Noah Baker

Okay, so you worked with rat models, then you moved to non-human primates and then you did test your system in a human patient. Tell me about that process because that’s the key moment for any clinical researcher, the first time they get to test their system in a human patient.

Interviewee: Grégoire Courtine

It’s true. It’s a moment I have already experienced when I was working with the recovery of walking, paralysed people making their first steps when we turn on the stimulation, and the same happened with the one patient. So, this is actually a surgeon in Calgary, and we couldn’t test all of the features of the neuroprosthetic baroreflex, so we could only test the basic features, but for him it was sufficient to really dramatically change his quality of life and since then, he has completely stopped medication. He is using the stimulator whenever it’s necessary for him to modulate his blood pressure, and that’s really changed this one aspect of his life as a person with a spinal cord injury.

Interviewer: Noah Baker

I mean, that’s exactly, I suppose, what you as a scientist and a clinical scientist wants to hear with your work. I’m always conscious in these kinds of situations that it’s very rare to find a win that doesn’t have other things to think about. There’s almost always some form of side effect. Are there side effects you’re concerned about? Chronically stimulating these neurons, could they perhaps have impacts on other parts of the body?

Interviewee: Grégoire Courtine

There is a concern that by stimulating constantly or maybe also over-stimulating that you can damage other organs. But also maybe more importantly, you may receive what is called autonomic dysreflexia, which is a very unknown phenomenon, but people with spinal cord injuries are very much aware of it, meaning stimulus – typically a bladder infection or like constipation, for example – will activate the blood-pressure system and elevate suddenly the blood pressure. This could lead to a stroke and people die because of autonomic dysreflexia, so of course there is a concern that by using our stimulation we can facilitate autonomic dysreflexia and this is certainly an aspect we will investigate in the future.

Interviewer: Noah Baker

And so, what’s next for your neuroprostheses? Is it a case of testing in more people or is there more you can do to develop and refine the system that you currently have?

Interviewee: Grégoire Courtine

So, for us, the next steps are two-fold. There will be large clinical trials in the United States in order to really establish a prosthetic system that can be used for all the people. And then a second part that is really exciting also, we propose a program to really act very early after the injury, with the same technology but implanted right away to really maximise the management of blood pressure in the first days, weeks, months after the injury and really improve the functional recovery. So, this is a very exciting time for this type of research because we can really foresee one treatment within the next two years for people who are suffering from chronic hypotension and maybe within the next five years, an intervention to help in the very early stages and improve recovery.

Host: Shamini Bundell

That was Grégoire Courtine talking to Noah Baker. You can read more about the synthetic baroreflex in his paper. We’ll pop a link in the show notes.

Host: Nick Howe

This is the point in the podcast where we’d usually have our weekly coronavirus news update, Coronapod. But as I’m sure many of you are aware, there’s a lot going on in the world with regards to COVID-19 right now. So, to cover all this news, Coronapod will become a separate show once again for the time being. It will be coming out later in the week, so make sure you keep an eye on your podcast feed.

Host: Shamini Bundell

Coming up in this show, how do you understand what other people believe? It’s a pretty complex skill, but scientists have mapped the neurons behind it. Right now, though, it’s time for the Research Highlights with Benjamin Thompson.

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Benjamin Thompson

This being a podcast, you can’t see me while I’m speaking to you. But if you could, you’d see that I’m actually using rather a lot of hand gestures to emphasise words as I’m saying them. Perhaps this makes me look a little bit silly alone in my room, but it turns out that gestures like these could be playing a subtle but important role in how words are perceived. Researchers in the Netherlands asked volunteers to watch videos of a speaker who used a common type of up and down hand movement while talking, known as a beat gesture. These participants were then asked to report on the syllables the speaker stressed or the duration of the vowel sounds that they spoke. When people heard a syllable that coincided with a beat gesture, they perceived it to have more emphasis and also the vowel sounds within it seemed shorter to them. Both effects were subtle but have the potential to drastically alter the meaning of an entire sentence. Consider the shift in emphasis from ‘OB-ject’ to ‘ob-JECT’, for example. The study bolsters theories suggesting that language comprehension is about more than just what you hear. You can’t see me but I’m gesturing over to the Proceedings of the Royal Society B where you can read more.

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Benjamin Thompson

Saturn is a planet that’s not on the level, but what made this planet such a pushover is a subject of some debate. Saturn is tilted with respect to its orbit around the Sun. Planetary scientists had thought the planet acquired its tilt more than 4 billion years ago thanks to the gravitational influence of Neptune. But now, a new theory suggests that the tilt happened much more recently and that Saturn’s biggest moon, Titan, is to blame. Recent measurements show that Titan is moving relatively rapidly away from Saturn. Using this information, researchers were able to determine that 1 billion years ago, as Titan moved away, it reached a position where its gravitational influence made Saturn unstable, making the planet wobble on its axis until it ended in the jaunty tilt we see today. The team suggests that the tilts of giant planets like Saturn could evolve over time as their moons migrate. Head over to Nature Astronomy to read more.

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Interviewer: Nick Howe

Whilst it may not always seem like it in today’s modern world, humans are really good at understanding that other humans have feelings, thought and beliefs that may differ from our own. We’re even good at grasping what they may be.

Interviewee: Ziv Williams

So, a very common example would be something like you’re sitting with a friend and you’ll see them reaching for a glass of water, and based on that you may infer that they’re thirsty.

Interviewer: Nick Howe

This is Ziv Williams, a neuroscientist from Harvard Medical School in the US. He’s interested in understanding the neurological processes behind this ability known in psychology as theory of mind, an important skill for all sorts of cooperative behaviours that humans are famous for. And this week in Nature, Ziv has published a paper that’s finely detailed the individual neurons involved in this process. I called him up to find out how he did it, and started by asking what we already knew about how this complicated process works in human brains.

Interviewee: Ziv Williams

So, there have been functional imaging studies that have shown some parts of the brain that light up when people try to think about other people’s beliefs, but until now it hasn’t really been clear whether or how are neurons able to represent another’s beliefs which are inherently unobservable and unknown.

Interviewer: Nick Howe

And so, we have like a general understanding of maybe parts of the brain that might be involved in this process, but in your paper you’re really trying to identify the individual neurons that are involved.

Interviewee: Ziv Williams

Correct, yeah, and neurons are interesting because these are really the simplest units in the human brain that are able to encode any kind of information, and it’s a little bit like computer transistors, 0s and 1s, and by being able to record from these individual neurons, you can start asking very interesting questions about what are the basic computations that allows the brain to form these kinds of representations and predict what somebody else is thinking.

Interviewer: Nick Howe

And so, how do you go about trying to find this out? How do you identify what neurons are involved and how do you test it in people?

Interviewee: Ziv Williams

So, what we do is we record from neurons in participants that are undergoing neurosurgical procedures, and as part of standard medical care we are implanting microelectrodes to record neural activity in their brain, so these very, very fine microwires that we put right next to the brain cells and they’re able to record the activities of those individual neurons. So, what we do is record neural activity from parts of the brains that are thought to be involved in theory of mind, and as we’re performing recordings from these individual neurons, we are having the participants perform this social behavioural task. So, for example, we use this false belief task that basically poses narratives to individuals, so a participant may hear a narrative such as, ‘You and Tom are sitting at a table and when they leave you move a cup from the table to the cupboard,’ and we can actually track the activity of individual neurons as they are forming inferences about these situations. And so, when we ask a question like, ‘Where does Tom believe the cup to be?’ you can actually ask how is this neuron changing in its activity based on changes in the others beliefs.

Interviewer: Nick Howe

So, after mapping what these neurons were doing and which ones are firing, what did you find? What parts of the brain or what neuronal processes were involved in theory of mind?

Interviewee: Ziv Williams

We found that there are certain subgroups of neurons kind of right in the front and middle part of the brain that would only activate when thinking about somebody else’s beliefs, but they displayed fairly little change in activity when thinking about anything else. The other really interesting thing was that they did this really reliably. So, we presented the participants with richly varied narratives. In some cases, they were thinking about the location of a car or a bicycle, and in other situations are thinking about a present that was being given to a friend, and in other cases they may be thinking about the location of a drink on a table, for example. But throughout all these situations, these neurons very reliably tracked what the other believed about these things. But we also found other neurons that very reliably predicted what it is that the other specifically was thinking about. So, we have these multiple subgroups of different neurons, each doing slightly different things, so when you glue these all together they painted a very rich picture of what it is that the other individual believed.

Interviewer: Nick Howe

Were you surprised at this because to me as a layperson it seemed almost inconceivable that what sounds like a very complicated neural process can be boiled down to just, well, it’s several hundred neurons, but still, like a few neurons in the brain. Were you surprised at this at all?

Interviewee: Ziv Williams

Yes and no. So, one of the interesting things about neurons is what we’re doing is we’re basically reading out information from these individual nodes, but each neuron is part of a vast network of other cells that all are doing presumably slightly different computations. It’s not like these individual neurons are likely coming up with these very complex predictions on their own. They’re likely integrating information from other parts of the brain, and if we had access to every cell in the brain we could probably paint a much richer and more complex picture of what other people are thinking and what I’m thinking as well. But this is a good starting point. It lets you start peering into the brain and looking at what neurons are doing and how they’re representing information about these extremely complex, higher-level-type social representations.

Interviewer: Nick Howe

I was wondering as well what might be the implications of this? What does this add to the sort of understanding of theory of mind and to sort of neuroscience more generally?

Interviewee: Ziv Williams

So, theory of mind is really central to a lot of aspects of social behaviour. So, it’s essential to our ability to interact effectively, to cooperate, and so it’s important to be able to understand what are the basic computations that underly this ability for us to be able to understand how people are able to do these things. It is also important for our understanding of how are individuals able to feel empathy for others or to feel what somebody else is feeling even though that may not be explicitly stated. But more importantly, theory of mind is also often affected by disorders like autism and in autism especially, this is one of the aspects of this disorder that is most disabling, the inability to socially interact effectively with other individuals, and so by starting to get us an understanding of what are the basic units and elements in the brain that are responsible for these basic social computations, it can allow us to begin building a blueprint for not only how the brain performs these computations but also what aspects of it may be disrupted by disorders such as autism.

Interviewer: Nick Howe

That was Ziv Williams from Harvard Medical School in the US. To understand what he thinks about theory of mind, check out his paper in the show notes.

Host: Shamini Bundell

Finally on the show, it’s time for the weekly Briefing chat were we discuss a couple of articles that have been highlighted in the Nature Briefing. Nick, what’s hot in the world of science?

Host: Nick Howe

Well, what I’ve been looking at this week is a story in Science, and it’s about cats’ obsession with catnip.

Host: Shamini Bundell

The fact that cats like catnip is basically the only thing I know about catnip because I’ve only ever heard people use it as a metaphor for something you really like. You’re like, ‘Oh yeah, it’s like catnip to me,’ and I’m like okay, I know that that means you like it. I don’t know why.

Host: Nick Howe

So, you’ve clearly never had a cat. So, this is a common thing – it comes from a plant actually – that’s put in cat toys and stuff, and basically they just go wild for it. They’ll grab whatever it’s in, rub it all over themselves and just basically squirm all around the floor and just, yeah, they go absolutely wild for it. And it’s often described as things like ‘kitty crack’ and that sort of thing and, well, this story is trying to work out why that is, and it seems like calling it kitty crack is probably not too far because it similarly affects cats’ opioid systems like morphine and heroin do in people.

Host: Shamini Bundell

It’s actually cat drugs. It’s just like… are they going to get addicted to it and it makes them feel good? That’s terrifying.

Host: Nick Howe

It does sound terrifying when you put it like that, but this study wasn’t really looking at how addictive it is or that sort of thing. It was looking at what the sort of mechanism is behind it. They seem to have boiled it down to a couple of compounds – nepetalactone and nepetalactol seem to be the key ingredients. And so what they did to find that out was they basically put little dishes, one that had been rubbed in this compound and one that hadn’t, in cages with cats, including big cats like jaguars and stuff, and also dogs and other animals, to see how they reacted, and just the cats, including the big cats, all reacted with the discs that had been treated with this compound and would like rub it all over themselves, but dogs and stuff, they weren’t bothered.

Host: Shamini Bundell

So, all of the cats are just really into the magical catnip compound. Is it bad for them?

Host: Nick Howe

Well, it might actually be good for them because whenever you see something like this you wonder if there’s like an evolutionary reason behind it, and it seems like there might be because in this study as well, they were wondering the same thing and they found out that it may actually repel mosquitoes, and so the action that cats do – they rub it all over themselves – may be protective to actually ward off mosquitoes because this compound, nepetalactone, has been used in pesticides, and so they thought maybe it will work with cats as well. So, what they did is they sedated some cats, would rub the compound on them, and then mosquitoes would land on them 50% less.

Host: Shamini Bundell

I imagine particularly for cats, if you’re sort of stalking your prey across the savannah, you don’t want to be itching small mosquitoes landing on you.

Host: Nick Howe

Yeah, exactly. They suggest that might be a reason why this trait has evolved because yeah, you don’t want to be jumpy when you’re trying to stalk something. But it’s not clear what came first, the sort of high that cats get from it or the rubbing it all over themselves to protect from mosquitoes. It could be one led to the other in the way that evolution so often does.

Host: Shamini Bundell

And now it provides entertainment when we can give it to cats in toys and watch how enthusiastic they are about it.

Host: Nick Howe

Yeah, although the description of like ‘cat heroin’ made me rethink that slightly.

Host: Shamini Bundell

Yeah, slightly off-putting.

Host: Nick Howe

Slightly off-putting. What have you found this week, Shamini?

Host: Shamini Bundell

So, the story that caught my eye this week was from SYFY.com and it caught my eye because it’s about a gorgeous image of a planetary nebula, which obviously, ideal for podcasts, talking about really pretty pictures. There’s a link to it in the show notes so you can go and have a look for yourself. And it’s sort of these huge, gorgeous swirls in space, and I realised I didn’t really know what a planetary nebula was so I’ve gone away and done some research and also read up on why this one is particularly mysterious.

Host: Nick Howe

Yeah, I must say I know nebulas as in where stars form, just these great, big dust clouds you see, but I’m not really sure what a planetary nebula is. So, yeah, please fill us in.

Host: Shamini Bundell

Yeah, so that’s one kind of nebula. It’s also slightly confusing because anything slightly fuzzy in the sky used to be called a nebula, so like spiral galaxies used to be called spiral nebula, the andromeda nebula, and then everyone was like oh, no, those are galaxies.

Host: Nick Howe

Classic science.

Host: Shamini Bundell

Yeah, so nebula tend to be clouds of dust or ionised gas sort of glowing faintly, and planetary nebula, just to make this more confusing, are nothing to do with planets, it’s just that when the astronomers first looked at them, they were like, ‘Oh, it’s round. It’s like a planet.’ It’s not, in fact, like a planet at all. It is this sort of big cloud of ionised gas and, in the case of planetary nebula, it’s gas that’s sort of ejected from the outer layers of giants, so like what our star will become as it sort of grows bigger and bigger, and then these stars also emit radiation which causes this gas to glow, which is how you can see them at least with telescopes. But they are very, very faint. So, this story is about a new planetary nebula that has been spotted and it’s so faint that they only were able to see it in an image which had an exposure time of 59 hours.

Host: Nick Howe

Wow, so this nebula was particularly faint. Why were scientists interested in it? Because it was unusual in that way?

Host: Shamini Bundell

Well, no, so, at this point, all people have done is basically spot it. So, some amateur astronomers have been combing through all this data, basically looking for planetary nebula because they are so hard to see, and this is a new one they’ve found. I think it’s particularly cool because it’s actually about the size of the full moon on the sky, so kind of huge but of course completely invisible to the naked eye. And the reason other astronomers are interested in it is that it’s a really peculiar shape.

Host: Nick Howe

Right, and you said they have these sort of round shapes normally so what sort of shape does this particular planetary nebula have?

Host: Shamini Bundell

Yeah, well, the first ones that were discovered tended to be these sort of nice bubble shapes, like you can imagine if a star is sort of growing and ejecting gas, it’s just this growing bubble of gas that you can see. And then they started finding ones of different shapes, so some of them might be a different shape because it was a binary star system, so there was some sort of spinning happening or because when the star, when the red giant, sort of was expanding, there was a big planet that got sort of absorbed into the star and changed its sort of speed or rotation or momentum, things like that. Or it could be some of them have shapes to do with magnetic fields, perhaps, of the star, perhaps even of the galaxy that they’re in. But this one is quite weird, so it’s got these very long, thin filaments which are quite unusual. It might be because of magnetic fields but it seems like it’s too big, potentially. It’s like surprisingly large so it’s quite tricky to calculate how big it actually is. So, there are a couple of stars which could be the sort of central white dwarf star around which planetary nebula form, and they’re not quite sure which of two possible stars it is, but either one, it’s really quite far away and really quite big, and there’s some questions there about how it could have got so big. It’s in an unusual place in the sky, so it’s not along the main plane of the Milky Way where most of the stars in our galaxy are, and the fact that it’s kind of off to one side maybe means it has more room to expand. Basically, there’s loads of questions and all we’ve really got so far is this sort of 60 hour exposure which sort of says, ‘Look, it’s there! Look, we found a thing!’

Host: Nick Howe

So, do astronomers and scientists have any idea how they might try and unpick some of these questions?

Host: Shamini Bundell

Well, there are lots of things you can do but it takes a lot of time and equipment to dig into this, so measuring the wavelengths of the light it emits would be a good one. That would take even longer exposure times plus a huge telescope, so it might be a matter of when someone gets round to it or whether it piques anyone’s interest.

Host: Nick Howe

Fair enough. Well, I look forward to hearing more about this bizarre-sounding planetary nebula in the future. But listeners, I think that’s all we’ve got time for, but if you’re interested in the stories we’ve discussed and you would like more like them, then make sure you sign up to the Nature Briefing. We’ll put a link to that, along with the stories we discussed, in the show notes.

Host: Shamini Bundell

That’s all for this week. But before we go, we do have a new film out. This one is all about the ears of prehistoric mammals and a particular kind of mammal whose ears may shed some light on when mammals originated as a group. You can find a link to that in the show notes.

Host: Nick Howe

Also, don’t forget to keep an eye out for Coronapod later this week. I’m Nick Howe.

Host: Shamini Bundell

And I’m Shamini Bundell. Thanks for listening.