Australasian Science Magazine

By Sila Genc

Magnetic Resonance Imaging, or MRI, has revolutionized modern medicine, allowing us to see detailed structure of the human brain. PhD students Charles Malpas and Bernd Merkel discuss their research into applying MRI as a tool to investigate diseased and healthy brains to help fine tune our understanding of how the brain works.

SILA GENC
Hello and welcome to Up Close. I’m Sila Genc, thanks for joining us.
Magnetic Resonance Imaging, or MRI, has revolutionised modern medicine, allowing us to see into the window of the human body. MRI of the brain has allowed for many different investigations of structure and function of certain regions of the brain, anywhere from visualising a stroke lesion to recognising abnormal function in epilepsy.
Over the decades MRI research has answered many questions into the development of the human brain and how this can be disrupted by pathology and disease processes. But many questions still remain unanswered. Are there discrete structural and functional relationships between different parts of the brain in healthy individuals, and how does this change with ageing and cognitive impairment?
Joining us today on Up Close for our annual PhD episode are two researchers who are exploring the complexity of the brain with Magnetic Resonance Imaging techniques.
Later in the program we will be talking to Bernd Merkel about the volumetric and structural changes seen by MRI in cognitively impaired individuals and how this can be impacted by lifestyle factors. But first we are joined by Charles Malpas who is using MRI as a tool to investigate the functional networks in the brain associated with intelligence in healthy individuals. Welcome to Up Close, Charles.

CHARLES MALPAS
Thanks Cilla.

SILA GENC
Charles, why don't you start off by telling us a bit about what MRI is and what it can tell us about the brain that we don't already know.

CHARLES MALPAS
MRI is sort of the latest in the methods we actually have to take pictures of the brain essentially inside the living human, which kind of sounds a bit strange but, you know, a hundred years ago if you wanted to see how the brain was structured you had to wait until someone died and then have a look inside their brain. But MRI allows us to look with really good detail into what's happening within the brain of the human being. And so we use that in many different ways. We can look at the structure of things in the brain, so how big certain parts of the brain are, how small they are.
We can also look at how things are actually activating and functioning when someone's doing something, like doing a task for example. So say I'm lying in a scanner, I'm thinking about playing tennis, then a certain part of my brain will be more active compared to other parts. So really it allows us to look at many, many different things and many different problems.

SILA GENC
Charles, you've told us about what MRI is; what is functional MRI and what's the difference between the two? Can we get a functional MRI at the same time you're just getting a normal MRI?

CHARLES MALPAS
Yeah, you can. So MRI describes the overall technique of taking images of the brain, essentially, so looking at brain structure and function. So it's a bit of an umbrella term. And whenever you think about MRI you think about the big MRI scanner in a hospital.
Functional MRI is just one subset of that. So for example, if I have a head injury, a hit my head and I go into a hospital, they might give me MRI and what they're really looking at are the structures of the brain. So for example, have I head damage to a certain area. Functional imaging is a little bit different. It's not just taking one snapshot picture of the brain, it's looking at how the brain changes over time. So with the kind of scans we do, we put someone in the scanner for, say, eight minutes and every two and a half seconds we take a snapshot of the brain and we can actually see how things are changing.
What we really look at is what's called the blood oxygen level dependent response. It's referred to as the BOLD response. It's easier to remember BOLD. That looks at how different parts of the brain might be using more or less oxygen, essentially. So we can see which parts might be more active or less active.
With functional connectivity analysis we use that information to work out which parts of the brain might be talking to each other. So if I have one part of my brain on the left-hand side and one on the right, and I see in the scanner that when the left-hand side tends to activate so does the right-hand side, then I infer that those two areas must be connected together. And what we say is that neurons that wire together fire together, essentially, so we're inferring some kind of connection based on which areas are co-activating together in the scanner. And that's the essence of functional MRI in the context that I use it.

SILA GENC
We hear a lot about functional networks in the brain, and normally when people talk about how the brain functions, they're talking about how you're functioning in terms of a task. So if you're shown certain pictures, how do you behave, or if you're shown pictures of nice food, how does that make your brain behave. But what do we know about the brain at rest and how our brain functions when it's not really doing anything?

CHARLES MALPAS
Yeah, this is the latest area of research in MRI. If you think about the brain as a big network, you know, the brain is really, really complicated. It has lots of different areas that are all firing and working at different points, and the idea is that they come together at some point to let us do things. So when we think a certain thought it's brain networks working together, different parts of the brain connecting to make us think or say something.
And so we haven't really been able to examine that in detail how those networks are really working. MRI now allows us to actually do that, to come together and see how do different parts of the brain talk to each when we're doing a certain task.
Resting state MRI is the latest application of that. so as you said, we previously could look at someone in the scanner - and let's say they were thinking about playing tennis, my favourite example - and we could see which part of the brain's activated. That is which part of the brain started using more oxygen and more metabolites when they're actually doing that task.
People started to realise not too long ago that they were sort of ignoring what was happening when people weren't doing a task. So when you're just sitting in the scanner, thinking about your day, your life, how noisy it was in the scanner room, that kind of thing, parts of your brain were still activated. That is parts of your brain were doing something. And people started to think what is that something? What's going on at rest and what can that tell us?
So recently we've been able to look at those areas that are activating when people are at rest and see what they relate to in terms of the real world. So for example, we know that people with certain psychiatric illnesses have different ways that their brain talks to different parts of the brain, talks to each other, at rest. And that can be used as a marker of people, of mental illness, for example.

SILA GENC
Charles, one part of your PhD is looking at functional MRI and how we can characterise intelligence and IQ. What have you found with this study and can IQ, or intelligence, be seen or characterised by an MRI?

CHARLES MALPAS
So IQ and intelligence is a really controversial area in science, and it has been misused. I like to talk about IQ. That stands for the intelligent quotient. That's that number people get on an intelligence test. There are some people out there who really believe that that number is intelligence, and that really sums up how smart you are. There are other people who are a bit more pragmatic, like me, who see that as a useful number. It sort of sums up how well you might do on lots of different tests of intelligence, but it may not actually be what we would think of in terms of everyday intelligence.
But it is a useful number, so we can use it for example in patients who are undergoing surgery for epilepsy. So there are some patients who will be going to have a part of their brain removed that's causing them to have seizures. And one thing we know, or we think we know, is that patients who have a higher IQ going into that surgery might actually do a bit better when they come out of the surgery at the other end.
The question is why would that be? Why would this number actually predict how well someone does after surgery? One of the ideas is that maybe that number is summarising how well all of the networks in your brain are actually working. And so when we measure someone's IQ before surgery what we're really talking about is how well the different parts of their brain are talking to each other.
And using that we decided to look at what networks in the brain are associated with IQ. It makes sense if IQ's picking up on those broad networks in the brain, perhaps we can actually image that, we can actually find those networks in generally healthy adults.
And so that's what we did. We had some adults there in the scanner, aged between about 21 and 55, so typical, healthy adults. And we found huge networks that were associated with how high or low your IQ was. That really supported the idea that IQ might be tapping into some kind of broad brain network that can tell us about something in health and disease.

SILA GENC
So I guess my question is, if we're finding these functional differences that are related to IQ, are there any structural relations as well? Are there parts of the brain that are connected together and that's what's leading to the function being connected together? Are they mutually exclusive elements or do they relate somehow?

CHARLES MALPAS
That's a really good question. We don’t know the answer to that question just yet. There is a big divide in terms of functional imaging and structural imaging. So functional connectivity is where we look at how the brain is activating together. So it's a very dynamic way of looking at how the brain activates and works.
Structural connectivity is a bit different. That's where we look at the white matter tracts in the brain essentially. So if you think about the brain being this big organ that's connected by this super highway of white matter tracts, that's what you're imaging with structural connectivity. I haven't really done much structural connectivity in my study, so we're not really sure how that plays out.
A few studies have looked at it and it does seem that the better the structures of your brain are connected the better they'll be functionally connected as well. So there does seem to be some kind of overlap, some kind of correlation. But it doesn't explain everything. So if I know how well the structure of your brain is connected together, I don’t know everything there is to know about the functional connectivity in your brain. So there are still some big questions there and we don't really know the answers yet.

SILA GENC
Another aspect of your PhD is looking into the changes in brains of people with Alzheimer's disease. What can you tell us about the function of the brain in these patients, and are the pathways associated with intelligence disrupted as well?

CHARLES MALPAS
It's another interesting question. The brain in Alzheimer's disease - Alzheimer's disease is a terrible disease of the brain and it does actually start to break down neural structures in the brain. In particular there are proteins in the brain which are like the building blocks of our brains. In Alzheimer's disease they start to get all tangled up and they break down. That's what causes things in Alzheimer's disease like memory problems that people experience and, later on, even more problems, so general dementia.
So in one sense, the breaking down of those networks is what explains what happens to people in Alzheimer's disease. And so we do use functional connectivity analyses to try and understand what parts of the brain are not working very well and which parts of the brain are trying to compensate in Alzheimer's disease for that as well.
For example, we looked at a drug treatment in Alzheimer's disease and we used brain network analyses to try and understand whether or not that drug was actually working. That is, the people who were taking the drug did they have healthier networks by the end of it compared to the people who didn't. Any time you see any sort of disease of the brain you can think of it in terms of some kind of network disruption.

SILA GENC
Charles lastly, where do you think research into resting state or functional MRI will take us? Can we combine this technique with other MRI techniques to give us a bigger picture of what's happening in the brain?

CHARLES MALPAS
Definitely, and that would be my hope of course, that everyone understands their brain network as imaged with MRI. I think the big thing at the moment is that we are using it in research settings quite a lot. So we're using it to understand how the brain works, especially in healthy people. We don’t use functional connectivity in a clinical sense. That is we don’t use it in patients who turn up to a hospital with a particular problem with their brain. And I think that's where we want to go.
We want to go to the point where you can use it as a clinical tool to help doctors understand what's happening with someone's brain and try and work out what the best treatment options might be. And that will be, I think, the big challenge over the next 10 or 15 years, is to take that into the clinic. So out of the lab and into the clinic and, hopefully, that's what I'll be helping doing at some level.

SILA GENC
Charles, thank you for coming in and talking to us about your research.

CHARLES MALPAS
No problem at all, thank you very much.

SILA GENC
Charles Malpas is a PhD student at the Melbourne Brain Centre, at the Royal Melbourne Hospital and the Melbourne School of Psychological Sciences at the University of Melbourne.
You're listening to UP Close. I'm Sila Genc.
Our second guest is Bernd Merkel. Bernd is doing his PhD on the applications of MRI on cognitive impairment and if physical activity can slow the progression of white matter lesions that can lead to Alzheimer's disease.
Welcome to Up Close, Bernd.

BERND MERKEL
Hi Sila, nice to meet you.
SILA GENC
Now Bernd, why don’t you start off by telling us what kind of changes can we see in MRI with people that have cognitive impairment?
BERND MERKEL
So if you're talking about MRI in people who are cognitively impaired or at risk of developing Alzheimer's disease, we have to differentiate between structural and functional MRI. So regarding structural MRI you can see in the images which we acquire from the brain that you have for example a shrink brain, what we call an atrophy, on the MR images and there are certain regions of the brain that are vulnerable and where you can see some tissue loss or damage. For example the hippocampus.
So the hippocampus is one region in the brain which is very early affected in Alzheimer's disease. People have found that out already years ago but these are the things that you're interested in when you're talking about structural MRI. So hippocampus and also the entorhinal cortex, where we see shrinkage and tissue damage and tissue loss.

SILA GENC
So if you were to do these measurements, looking at MRI - you want to see different structures of brains and how the shape changes over time - then is it possible to say look at someone that's cognitively impaired and follow them up in a couple of years and will you see visible changes; that their hippocampus, for example, has shrunk over time?

BERND MERKEL
Yeah, that's what you can see and what people have found out. They are also interested in the relation of the physical activity and hippocampus. Or there was recently a publication where people have seen that there are certain physical activity measurements, like people are asked to walk six minutes and then you're measuring how far they are walking. They found a relation between the size of the hippocampus and the sum of metres which they were able to walk.
That's definitely one thing you can look at. The other thing regarding structural MRI is white matter hyperintensities, where we can to see is there also a change in the brain with these typical characteristics.

SILA GENC
Bernd, oftentimes people think of grey matter in the brain, and you mentioned white matter hyperintensities in these people that are cognitively impaired. What's the difference between grey matter and white matter?

BERND MERKEL
So just very general, you can say in the grey matter you find the cells in your brain and in the white matter, that's how they are connected, the wiring and so on. So very easily I think you can say grey matter is the structure itself; and how these are all connected, that's more happening in the white matter.

SILA GENC
So what is a white matter hyperintensity? Are these the sort of things that you would see in cognitively impaired individuals? And can we see that on MRI?

BERND MERKEL
White matter hyperintensities are somehow you could say a permanent damage of the white matter of the brain. You can see these damages on a certain acquisition of magnetic resonance so they appear hyperintense. It's commonly accepted that those white matter hyperintensities are somehow related to an increased risk of developing Alzheimer's disease.
However, white matter lesions, or those hyperintensities, they also appear in normal ageing people. So it's not like you can say, okay, this person has a certain amount of white matter lesions, so he or she will definitely develop Alzheimer's disease. There's a lot more going on but it's one characteristic, like I said, of the hippocampus and the entorhinal cortex which is worth looking at with structural MRI.

SILA GENC
So Bernd, your research is particularly interested in looking at the impacts of physical exercise on the brain and the brain really in cognitive impairment. What has your research found so far? Tell us a bit more about the study you're involved in.

BERND MERKEL
So the study I'm involved in is called AIBL-Active. It's a sub study of the bigger AIBL study, so AIBL means Australian Imaging Biomarkers and Lifestyle Flagship Study. What we are doing is taking participants - so they all volunteers, about 100 - and they are all somehow cognitively impaired. That means they have marked cognitive impairment or subjective memory complaints but they haven't developed Alzheimer's disease yet, and they also have at least one vascular risk factor, like diabetes, blood hypertension or obesity.
That means they are all on a high risk of developing Alzheimer's disease but they haven't developed it yet. And the primary outcomes of this study is that we want to know over a term of two years half of those people undergo a physical activity program. So that means they are asked to walk 150 minutes per week and if they have already this certain level of fitness they have to increase it for 30 minutes. Then in the hospital we are acquiring images at a baseline and then two years later, and then we want to compare those images.
Of course, there is a lot more going on with the physical activity assessments. Blood is taken also looking at CSF biomarkers and so on. But that’s the primary outcome: can we see effect on the white matter hyperintensities with physical activity versus physical inactivity.

SILA GENC
Bernd, what do you expect to see at this two year follow up? Do we expect that the people that are having this physical exercise regime are not going to have as many white matter hyperintensities at two years and therefore have better cognitive function? Or do we expect that it might take a little bit longer to visualise these changes?

BERND MERKEL
When we are talking about the effect of physical activity, people say well so far we don't have any evidence that physical activity has an effect. What I'm looking at, at the moment, is just the baseline data. What we want to see is not a reduced number of white matter lesions over the two years but we would expect - because as I said, even in normal ageing people white matter lesions are there. But we want to see is the amount of white matter lesions over the two years increasing. Can we slowdown that with the physical activity compared to the people who are physically inactive.
There is evidence that there might be an impact but it's not for sure yet, and in the end that's why we are doing the study. Of course we can't say then physical activity will help you preventing Alzheimer's disease but it might be a proof of concept in whatever direction.

SILA GENC
Presumably, the size or volume of certain regions of the brain may take some time to change. Bernd, are there any other techniques of MRI that might be able to give us some more information on the impact of lifestyle factors and physical exercise?

BERND MERKEL
Yeah. So I was talking about the structural MRI already but there is also, as Charles mentioned, functional MRI. I'm now looking into arterial spin labelling. So this is a new method of measuring the cerebral blood flow, so the perfusion in the brain. But the advantage of this method is you don't need any contrast agent.

SILA GENC
By contrast agent you mean, say, an injectable dye?

BERND MERKEL
That's right. So if people think about perfusion, then normally people get a contrast agent and then you're waiting a bit of a time and then you're measuring how this agent flows through the brain and you're measuring that.
But with arterial spin labelling, you're labelling your blood magnetically and, as I said, no contrast agent. Then you're waiting a certain amount of time and then you can measure this labelled blood in your brain. The problem with this acquisition method is that it has a quite low signal to noise ratio.
So what it's done is, for example the study I'm working on, we have 50 times where we are measuring the brain with this magnetically labelled blood and without. And then we are calculating difference images, and that's needed to increase our signal to noise ratio because that's an issue with this method. But it's quite promising and that's what I'm looking at, at the moment.

SILA GENC
Bernd, thank you for coming in and talking to us about your research.

BERND MERKEL
Thanks Sila, it was a pleasure.

SILA GENC
Bernd Merkel is a PhD student in the Department of Radiology and the Melbourne Brain Centre at the Royal Melbourne Hospital, here at the University of Melbourne.