(0:09) James: Today, I am speaking to Topan Austin, who is online all the way from Singapore. Topan is one of the theme leads for the Life Course theme at the HealthTech Research Centre in Brain and Spinal Injury. So Topan, Life Course, are there particular periods of life where people are more likely to suffer some kind of brain injury? Is it more prevalent at particular age groups?

(0:33) Topun: I mean, it's a very good question. Yes, is the sort of short answer, and it's probably both at the start of life, and sort of towards the end of life. And it's the sort of age where the nature, and also the response to injury does sort of vary.

So I'm a neonatal doctor, so I look after newborn babies, and birth can be a sort of challenging period, both for babies born at sort of full term, but also a lot of babies (one in 10) are born prematurely. And they're sort of born into an environment they're not expected to sort of be in, and particularly that very fragile developing brain is having to sort of negotiate the outside world. So it is a particularly vulnerable time.

And similarly, at the other end of life, in the elderly, the sort of general degenerative sort of conditions that sort of people face as they get old, but also sort of ordinary activities that we take for granted (like sort of walking and things and having falls) the consequences for people who are elderly can be much more severe. So it's kind of important, I think, within the whole HTRC to sort of focus that actually age plays an important part because the type of injury and the response to injury will vary according to what happens.

(1:49) James: Yeah, so I guess your recovery from an injury when you're very elderly is going to be different (and probably a bit more complex) than if you're younger. And also you're more likely to fall over and bang your head because you've got those, kind of, frailties.

(2:00) Topun: Yes, and you may also, you know (falls are something which people sort of really focus on) the fall itself may be a sort of sign of something else underlying going on. So there's a condition of cervical myelopathy where your balance, your spine is sort of degenerating and your balance is sort of affected. So actually, the first sign can just be a fall. And people say, oh, they're just a bit old, they had a tumble, but actually further investigation showed that…

(2:30) James: That was something a bit more serious going on. Yeah. And I guess the other thing with elderly people is (often if we're trying to assess the impact of a brain injury) we would be doing some cognitive testing. But they may already have some cognitive decline or early dementia signs just because they're elderly. So it's much harder to kind of understand whereabouts people are in their journey.

(2:48) Topun: Absolutely, and I think that's really important. That's a really important point, to try and understand where is this person in their sort of normal baseline, and how are they following a sort of acute injury?

I mean, I can give a personal story of my mother who she had a number of falls (she actually had cervical myelopathy). And at one point she had pneumonia and it presented with confusion. And there was a kind of default assumption that, oh, she was just a batty old lady who was a little bit confused. And I said “No, this is somebody who was doing the Times Crossword a week ago. This isn't her normal baseline.” So trying to assess what's normal, what the acute sort of fall event has caused, can be sort of challenging.

And as you say, it's the response to injury, the rehabilitation and then trying to sort of, you know, ideally trying to avoid them getting into hospital. Once an old person is in hospital, it's really difficult to get them out again if you can avoid that. And I think part of the theme is trying to sort of get better sort of communications with the home, with social care and things, remote access. So to avoid those sorts of admissions.

(3:55) James: Yeah, and certainly we're seeing lots of interest in sort of tele-rehabilitation and avoiding taking people into hospitals. Hospitals are really dangerous places to go, aren't they? They're full of sick people, right? You want to minimise the time that you're spending in those places.

So you said that your specialist, mainly is at the other end of life, neonatal. What kinds of things are happening to these babies? Is it just that they're not fully developed, if they're early or do they suffer injuries during birth? You know, it's a traumatic time for mother and baby, isn't it?

(4:27) Topun: Well, it's both. So the newborn brain is both vulnerable to injury, but it's sensitive to repair. And, so you have one example, if you are, yes, born prematurely. And we'll look after babies from 22/23 weeks gestation (where full gestation is 40 weeks) so almost half the pregnancy. And these are very, very tiny babies, and their brains are undergoing remarkable sort of development in that period. And it should be happening in the dark, warm, wet environment of the womb, and not outside on the neonatal unit. So just from a purely developmental process, the environment this brain is developing in is abnormal.

But the trauma of being born, a very fragile brain (and there's lots of very fragile blood vessels and lots of changes that occur in the sort of physiology as you come in the outside world) puts these babies at risk of developing bleeds into the brain, and also a lack of blood flow to the brain (which can cause sort of permanent injury). So the premature baby is very vulnerable for that.  And then the course that they take on the neonatal unit, any sort of systemic illness (so if they develop infections, often they have trouble with breathing so they can develop lung problems) they all have a sort of knock-on effect to the sort of developing brain.

And the real challenge is trying to identify those ones who are going to be vulnerable to problems later in life, and it's that sort of prediction, you know. So, some of our very tiny babies, they actually seem to sail through, and when you follow them up, they go to mainstream school, they seem to do very well. Others actually have a real struggle. And some of them you can predict, but a lot of them, actually, it's very difficult to know where the trajectory lies.

(6:11) James: Yeah. And I guess perhaps some of the new innovations that we might see coming through are about that kind of identifying those issues early on that may well have consequences later on in life.

How do we go about sort of monitoring these tiny babies? We've seen the pictures in our minds, don't we? They're in an incubator somewhere. We need access to that child to see what's happening inside their head. Are there ways that we can do that?

(6:35) Topun: Yes, I mean, the standard ways of imaging the brain, we use ultrasound scanning (which is used when mums are pregnant, and they get a nice picture of what's going on), and the beauty of the newborn brain is that their skull is fused. So you have a little sort of window, where you can put an ultrasound scan on this fontanelle, and you can get a nice picture of how the brain is developing. And it's very good at sort of predicting whether or not the baby is developing a bleed into the brain.

You can also put babies into MRI scanners. But that's challenging to sort of move a baby down to an MRI scanner. They've got to keep still. And one of the things I’ve learnt is you can tell babies whatever they want, they'll just do their own thing. So, you know, it is a challenge. And so one of the interests that I've got and that the HTRC are sort of helping support is looking at ways (instead of so much assessing the structure of the brain, which we're good at) we’re looking at the function. How well is it developing? How well is it working?

And my background is in using light, using optics. I think most people are familiar with the pulse oximeter, which you sort of stick in your finger and it measures in sort of oxygen levels. We've been working with colleagues at University College London and developed a system which uses this light technology, but multiple light sources and detectors overhead, and it can measure blood flow in different parts of the brain. And we're now trying to combine this with a new kind of ultrasound system, which gives very detailed pictures of blood flow in the brain. And, using those technologies together, we hope to get a sort of image of brain function, and, hopefully, be able to diagnose those infants who may be developing problems, but also just see that sort of development. In the way that we sort of plot growth over time (you plot development over time), and see if there are some babies who are not developing brain function in the way one would sort of anticipate.

(8:22) James: Yeah, because I guess when babies are between one or two, their brains are making more connections than any other time in their life, right? They're building these neural pathways and developing. So we need to know whether that's happening on the kind of normal way we'd expect it to or maybe something's kind of interrupted that process.

(8:38) Topun: Yeah, I mean, the figures are astonishing. You're making something like a million synapse (these little connections between brain cells), the premature and the newborn baby, about a million a second. And when you look at a baby, they all look very cute. They're all just sleeping there, lying in a cot. What you don't realize is that there's a furnace going on inside of activity, which you, as you say, you never see the rest of your life.

So ensuring that that can happen in a sort of protected way is something which is kind of really fundamental. And one of the areas that we got quite interested in is something so obvious. Why do babies sleep? It actually turns out, sleep in a newborn is very different to sleep at any other stage in life. They cycle through sort of different phases of sleep every hour or so. And they are making connections, they are wiring up their brain. And it's something, we don't necessarily sort of monitor the different sleep states that they are in, we keep interrupting sleep states. And, I think we all know what it's like when you have an interrupted night's sleep, very grumpy in the morning, but our brains aren't wiring up! You imagine if your brain is wiring up and you're having interrupted sleep. You kind of think “ahh”.

So it's simple things like, can we protect sleep? Would that help protect brain development? (James: Yeah.) Very easy intervention. But it just requires, it's where technology would come in, where we could easily monitor sleep, and get an assessment and help the nursing staff know what the baby needs.

(10:11) James: Yeah. Fascinating. I'm just thinking about the amount of times my baby's interrupted my sleep! That is fair, right?

I guess the next question is, what do we do? So what kind of interventions and treatments can we give these tiny babies, if we notice perhaps that things aren't developing in the way we'd expect them to? Perhaps their brains aren't making those connections at the sort of rate we'd like to see. Is there anything that we can do to change that?

(10:43) Topun: The field is quite expansive. So everything from, people are looking at things like stem cells, other neuroprotective drugs which can help the brain development, on one side, what I call a quite, sort of, interventional medical approach to dealing with brain injury (and there is some sort of promising research in that area). Through to what I would describe as a more naturalistic way of helping the brain develop. And one of the areas is around, what we call, family-centred care.

Because, what happens when you have a very sick or premature baby, is that baby rushed to the neonatal intensive care unit, separated from the mother and the father and the rest of the family. And, while we encourage visiting and things, that social contact is often fragmented. And that has two effects. One, for any parent who's had a baby on the neonatal unit, it's a really traumatic experience. And for a mother, having a sort of post-traumatic stress following the birth of their baby, can have real implications in that early upbringing, that they can sort of, it's very well documented. Mothers who have depression during or after birth, their offspring have a much higher risk of mental health problems into sort of young adulthood. So helping, supporting parents actually not only improves the life of the mother, but it improves, protects the baby.

But also there's something (and this is something I'm quite interested in) something fundamental around mother/infant (I'm going to say mother, but caregiver) you know, human contact between the baby. And yeah, we are social animals. And the babies are totally dependent on their caregiver. But not just for nutrition and things, but for that whole learning about the world, and that early social contact. And to try and encourage that early on may, actually not just be a nice thing to do (a sort of human thing), but it actually might be crucial in the way the brain is developing. So we're doing some work here in Singapore, looking at the way the brain of the caregiver and the baby sort of, almost, communicate with each other in those early stages, which may have, sort of much, more beneficial effects.

So as I say, there's sort of medical treatments to sort of help the brain develop. But I think both in the neonatal period and in this first year or so, the contact can sort of help improve the sort of potential.

(13:12) James: Yeah, I think I'm right. There's some kind of evidence of that coming through because of Covid, of course. We had a lot of babies born who couldn't get that social contact with family and caregivers because we were so terrified of spreading this awful virus around. And I guess that's a kind of indication that we've got to be careful about this. We can't just isolate these babies. We need to have that contact.

(13:36) Topun: No, absolutely. And I was fortunate to be involved in a project with the Department of Psychology here. It was called the Cocoa Pip Study, where we sent out a survey to newborns or mothers who were pregnant, or had young infants, during the first lockdown period to gauge their experience of the whole sort of process. And it was that social isolation, both for the mother, but as you say, early for the infants. And I think it's now coming through. One, the normal social development, so when babies are sort of firstborn, they'll smile at everybody and they're very interactive. And then as they get older, they get that sort of stranger awareness. And that stranger awareness seems to have been sort of negated a bit because they're just not used to seeing people and knowing who's friendly, who's not. And also language delay; everyone is wearing masks and part of language is lip reading. We take it kind of for granted, but it's much easier to hear somebody (I say there's some half-deaf, but even people with normal hearing) to have that lip reading. And so children are socially not being exposed to a lot of different voices. So, yeah, it was a horrible natural experiment as to what happens if you sort of socially isolate young infants.

(14:50) James: Yeah. And I guess, if we can pull anything good out of this awful time, it's that we've learned this stuff, and we understand kind of how important it is. And I think it'd be really interesting to see the kind of things that you've been talking about with these very premature babies who are really struggling to develop, actually what they need is a cuddle, right? They need some contact and they need to see people's faces and kind of engage.

(15:14) Topun: Yes, absolutely. And it's seen, I had a student who just finished her PhD looking at the sort of brain synchrony between mother and infant during social contact and affectionate touch. And showed that during affectionate touch, there was more synchrony. And I remember when she was presenting her results (and this was very clever, EG data processing and things) it kind of said babies like being cuddled. Who knew? It's so obvious.

But trying to understand that underlying neuroscience, I think, is really important because then we can relate that to the more vulnerable patients. And also how we should then approach sort of both designing neonatal units, providing the care, providing the support. Because one of the real challenges, keeping parents together with their baby, can be actually more challenging. And so to actually show to you this is important, we need the resources to sort of support these, whether it's with travel, whether it's childcare, etc. Not just because it's nice, but actually it's vital to improve the sort of outcome for these children that early.

(16:21) James: Yeah. And I guess there's an interesting sort of, probably we'll go back to where we started with those elderly people. Because, similarly, you don't want to be a hundred miles away from your family, even though that's, ‘the best hospital for you to be in’. Actually, you also need that human interaction, you need to be with family. And that can be a challenge sometimes.

(16:38) Topun: Absolutely. I mean, and again, Covid was a horrible sort of petri dish for experimenting on that. The sort of, social isolation that elderly people are having to face when that's what they needed, they needed social contact. And again, technology can be really helpful. I mean, I know that from my own experience, just, you know, having FaceTime. I remember when FaceTime first came about, it all was a bit Star Treky and thinking “well, why would anybody want to look at me when I'm talking to them?”, and now I find it kind of slightly odd. But it was great for my mum to, sort of, see her grandchildren and things, even though she couldn't sort of physically be there. But that importance of physical contact, I think, has been clearly shown to be important and how we can sort of support that. And exactly as you say, you can avoid them coming into the hospital, not only is it a dreadful place to be in for their health, but it stops them from moving from home if you can treat them remotely. Yeah, and support them that way.

(17:37) Yeah, and some kind of “real win”. So I guess the HRC is going to run for five years. Do you think that, in five years time, the world of neonatal brain injury will look quite different from the way it is now? Are we going to see new innovations, new treatments coming through?

(18:00) Topun: The million-dollar question! I think there are areas where, I think we are going to see, sort of, both a slow evolution, and also rapid change. I think we are moving much more towards this sort of family-centred care, and I think that's going to get much better. One of the projects which the former HRC supported and helped with was an app called Little Journey, which was just a sort of digital, we called it a digital helping hand for families. So those sort of technologies where we can bring families together, that's going to carry on that sort of journey.

This improved imaging is a specific project which I'm involved in, so I would like to tell you, “yes, this is going to really be a big thing”. But I know that translating technologies is a slow process, we need some proof of principle, does it work? Then we need to do larger studies, but I hope that that will go on.

I think the next area, which, again, we were involved in with the previous HRC, is looking at genetic diagnoses. The whole genetic revolution has really focused a lot on the newborn period. So we were part of a study, called the Next Generation Children's Project back in 2018, where we screened a whole group of newborn infants on the neonatal unit. And a significant number had specific genetic diagnoses, which (by having a rapid screening) we could action on, whether it would be sort of changing the management, or sometimes providing counselling for future pregnancies. That's moving into a new phase, the Generation Project, where we're looking at whole genome screening for all babies. So all babies in the UK currently will get a little heel prick on day three, or so, of life. And that for a specific number of conditions, such as hypothyroidism or a condition called PKU, where if you diagnose it early, treat it early, you can prevent long-term problems.

So the next idea is that actually, if you do rapid whole genome screening and you choose a number of rare diseases, but cumulatively. So that individually might be rare, but actually all the rare diseases together is not insignificant, there's a selection of those where early intervention can sort of early diagnosis can sort of help with outcome. And the idea is that we could screen all newborn babies with this test. Which is quite remarkable! I mean, the first whole genome sequencing took, I think 10 years, and cost a billion dollars or something, and now we're saying every baby could have it and get a return in a couple of weeks,  You know, it shows how it’s improved. The pilot study for that has just been launched. So I would anticipate, answering your question in five years time, genomic screening will be kind of a routine part of sort of early life care.

And also, I think from, you know, for parents getting a diagnosis, when is the right time? That was one of the things we learned from the Next Generation Children's Project. That we could give a diagnosis, and these could be quite profound diagnoses. Usually not, but sometimes it would affect the newborn at that point (and that's a different matter). But sometimes it would say, “Well, this is associated with problems later on in childhood”. And you've got a lovely, cute little baby, and it's very difficult to sort of, you know? And I know one of my colleagues is just completing a PhD looking at the family responses. And how that the diagnosis affected them? And did we tell them at the right time? When would be the best time to sort of counsel? So genomics is a bit of a Pandora's box. The box is open and there's a lot of benefits, but we do have to sort of tread carefully.

(21:53) James: Yeah, we need to be careful how we do these things. And we kind of keep coming back to this family-centred idea. Which I think is lovely, actually. It's about cuddles, alongside this really kind of innovative, high-power technology and understanding. Genomes are enormously complex things and understanding that has undoubtedly had huge benefits for human health right across the ages. We need to keep that alongside this idea that we are social creatures. Right. And often the best way to help people is we just help people. We smile at them. We talk to people.

(22:30) Topun: And I think one of the nice things with the life course, is that actually, there is so much overlap (especially in the sort of more social aspects) between the start of life and the end of life. You know, it goes back, as you say, to that sort of social communication, and what do elderly people need? What does the diagnosis mean? What is a good quality of life? You know, because you're 95, does that preclude you from an operation? Or if you've got a very poor quality of life at 75, do you have to, you know? And how can you ensure that the patients retain their autonomy, their capacity, et cetera, to make those sorts of decisions and not being afraid of having those conversations?

(23:11) James: Fantastic. Well, it's been a fascinating conversation, Topun. Thanks ever so much for tuning in from the other side of the world to talk about the Life Course theme in the HealthTech Research Centre. Thanks so much.

(23:18) Topun: Thank you.