Delving into memory to understand schizophrenia

CHRIS HATZIS
Eavesdrop on Experts, a podcast about stories of inspiration and insights. It’s where expert types obsess, confess and profess. I’m Chris Hatzis, let’s eavesdrop on experts changing the world - one lecture, one experiment, one interview at a time.

Up to 1 in 100 people worldwide will experience schizophrenia. It can stem from a number of factors, including genetics, trauma, and substance abuse. For centuries there’s been limited understanding of how schizophrenia operates, leading to misdiagnosis or insufficient treatment.

CASSANDRA WANNAN

I'm Cassandra Wannan, I'm a PhD student at the Melbourne Neuropsychiatry Centre, so we're part of Melbourne Uni's Department of Psychiatry.

CHRIS HATZIS
In order to better our understanding of schizophrenia, Cassandra Wannan recently authored a paper on schizophrenia and memory impairment. Confirming the role of memory loss in schizophrenia may be a major step towards fully understanding the illness. Andrea Horvath caught up with Cassandra to get the low-down on her exciting new thesis.

ANDI HORVATH
Cassie, what is the thesis title?



CASSANDRA WANNAN
Well, that's a really good question. I haven't come up with a complete title yet, but I'm looking at memory impairment in schizophrenia and how that relates to brain changes that we see in the disorder, so maybe something like neural correlates of memory functioning in people with schizophrenia.

ANDI HORVATH
Wow, that's a lot of jargon. Let's unpack that.

CASSANDRA WANNAN

Sure.

ANDI HORVATH
You're essentially looking at memory impairment in schizophrenia.

CASSANDRA WANNAN

That's right.



ANDI HORVATH
How do you do that?



CASSANDRA WANNAN
Well, we get people who have schizophrenia and we ask them to do some memory tasks pretty much, so we have this computerised task that we ask people to do, and we see how they're performing. Then we very kindly ask them to get in an MRI machine, which most people don't enjoy all that much, it's very claustrophobic. Then we have pictures of their brain, we have a snapshot of how their memory is functioning and then we try and tie those things together.

ANDI HORVATH
Cassie, why is it important to understand the brains of people with schizophrenia?

CASSANDRA WANNAN

Well, we see these symptoms, we see these psychotic symptoms, so hallucinations, delusions and we see these cognitive symptoms, so memory impairments, impairments in executive functioning and planning things, and these symptoms obviously impact on people's lives but we need to take a little bit of a step back and understand what's going on in the brain in the hopes that we can treat some of these different symptoms. So I think if we don't have a really good understanding of what's happening in the brain, we're maybe missing one of the crucial steps that we might need in order to discover how to help people with the disorder. So sometimes if you find an impairment in a certain brain region, you can then dig down a little bit deeper, think about what sort of chemicals you might find in that area of the brain, what neurotransmitters you might find in that area of the brain, and that kind of gives you some clues as to what you might be able to use to treat some of those symptoms.

ANDI HORVATH
The current treatment of people with schizophrenia is a drug, isn't it, or a range of drugs?

CASSANDRA WANNAN

That's right, so people with schizophrenia are usually on antipsychotic medications.

ANDI HORVATH
Are these not enough for treating schizophrenia?



CASSANDRA WANNAN
No, so, I mean in some people they are, that's definitely true, but there's - well first of all - there's a significant number of people who don't actually respond to antipsychotic medication, so we call those people, people with treatment-resistant schizophrenia. The other caveat is that a number of people with schizophrenia, although their psychotic symptoms might be treated, there's a whole range of other symptoms that aren't treated by the antipsychotic medications. So cognition is one of those things that isn't really improved by antipsychotic medication and another one is negative symptoms. So we often see a lack of motivation, some sort of depression in people with schizophrenia and these things aren't really treated by the antipsychotic medication, so there's something else going on there.



ANDI HORVATH
Tell me more about the memory in people with schizophrenia.



CASSANDRA WANNAN
Yeah, sure. So people with schizophrenia often present with cognitive impairments and these impairments are seen over quite a wide range of cognitive functioning. But one of the main ones that we do see is memory impairment and if you think about how often you use your memory every day, obviously you don't even think about the fact that you're using it, but you need to use your memory to get to work, you need to use your memory to remember what to put on in the morning, and if you weren't able to do this, obviously you would struggle. So there's pretty strong links between memory impairment and the ability of people with schizophrenia just to function on a daily basis. So that's kind of one of the reasons that I was really driven to investigate what was going on with memory impairment in schizophrenia.
 


ANDI HORVATH
So how do you explore the memory of people with schizophrenia?

CASSANDRA WANNAN
Well we use a computerised battery, and the one that we used is called the CANTAB and I've been looking at a couple of different memory tasks, none of them are particularly fun to do, but we have our people with schizophrenia and we sit them down in front of this computer and we ask them to sort of press these buttons when they see something appear on the screen that they've seen before and that's how we get a snapshot of how their memory is functioning.

ANDI HORVATH

Now you also take pictures of the brain.

CASSANDRA WANNAN
Yeah, that's right. So we ask our participants to have an MRI scan and I'm always surprised that everyone's quite willing to jump in the MRI scanner because I myself, I'm quite claustrophobic and I have no inclination to get in there.

ANDI HORVATH
Me too.



CASSANDRA WANNAN

But yeah, we've been really lucky and we have collected a couple of hundred, I think by now, MRI scans from people with schizophrenia and from healthy people so we could do a little bit of a comparison between the two.



ANDI HORVATH
So give us a peek preview into the initial results that you've seen of patterns in the brain of people with schizophrenia.

CASSANDRA WANNAN

Sure, well so one thing that I've really been looking at, given that I'm looking at memory functioning, is the hippocampus. So there's quite a few studies now that have looked at this area of the brain in relation to memory functioning and schizophrenia, but I wanted to dig down a little bit deeper and look at particular areas of the hippocampus. So this little tiny structure in your brain actually is made up of several different regions and we call them the subfields of the hippocampus and I wanted to know whether it was just one particular subfield, was it all of them, what was the relationship between these subfields and memory and people with schizophrenia. What I found was that there was actually two little subfields of the hippocampus that actually seemed to be quite strongly related to memory impairment in schizophrenia. So for those who are interested, the stratum and the dentate gyrus showed that they were two key regions for memory in schizophrenia.

ANDI HORVATH
Tell me more about the connections in the brain too, because I know you've been looking at those.

CASSANDRA WANNAN

Yeah, that's right, so this is sort of a little side project and not necessarily related to the cognition work that I've been doing, but when I started my PhD, I had this grand plan of looking at grey matter in the brain. If you don't know what grey matter is, it's sort of the outer surface of the brain, it's the cell bodies basically and these cell bodies are all connected to each other throughout the brain by something called white matter and they sort of form these little highways between different regions of the brain. People with schizophrenia, they have quite serious loss of grey matter in their brains and what we see is that as the illness progresses, this loss of grey matter actually gets worse, so people who have only just been diagnosed with schizophrenia tend to have a little bit of grey matter loss and then as they will progress through the illness, they tend to have more and more loss of grey matter over time.

ANDI HORVATH
So they're losing some of these pathways between the brain?

CASSANDRA WANNAN
Well that was one of the hypotheses, so that hadn't really been investigated and that was something that I was really interested in finding out. So there is this hypothesis that we see this grey matter loss in brain regions that aren't necessarily right next to each other, so what we wanted to know is, well what's going on there. If this one region at the very front of the brain and this one region sort of at the side or towards the back of the brain are losing grey matter, is it just random or is it actually a result of disruptions to connectivity between those two regions? So we were lucky enough actually to get three samples of patients to sort of replicate this study on and what we did is we looked at regions that had lost grey matter and then we just looked at whether they were more strongly connected to each other and that's what we found to be the case. So we did have quite strong evidence that grey matter loss was related to brain connectivity.

ANDI HORVATH

Gosh, that must be exciting to find a clue to memory loss for people with schizophrenia.

CASSANDRA WANNAN
Yeah, very much so and I guess it's really nice because it is quite applicable to a number of different areas. So you might might look at one particular area of functioning and one particular brain region and try and tie those together, but what we're thinking now is that it's not really enough to just look at one region of the brain and try and tie that in. So we really need to look at what's happening with all the regions that are connected to your area of interest to see what's going on there, is there a disruption in connectivity and is that what's causing some of the symptoms that we're seeing?

ANDI HORVATH
You're like a biological detective, trying to work out the pathways that need a little bit of fixing up. Is that the long-term goal?



CASSANDRA WANNAN
Yeah, definitely. So at the moment I'm working on a new project that's looking at connectivity between the hippocampus and the prefrontal cortex and I'm hoping that I can tie that into memory impairment in schizophrenia. So I'm really trying to dig down into this sort of memory pathway to see what's going on there.

ANDI HORVATH
These are very early days, as you've just established this pattern in the brain for people with schizophrenia. What are the possible long-term future solutions? What would you like to see we could sort of herald ourselves into the future? Are there possibly drugs that might be involved? Are there behavioural tasks that they may need to do to use neural plasticity?



CASSANDRA WANNAN
Yeah.

ANDI HORVATH
Or is it the old chestnut of diet and exercise?

CASSANDRA WANNAN
Well, I mean diet and exercise, very important. I think that's something that's often overlooked.

ANDI HORVATH

That's a given.

CASSANDRA WANNAN
Yeah, it doesn't matter, you know, I guess what illness you have, diet and exercise are always helpful.



ANDI HORVATH
I just throw it in because it comes up in every interview.

CASSANDRA WANNAN
Well a friend of mine and I did come up with this sort of harebrained scheme that we were going to start this exercise program for people with schizophrenia. Given my interest in the hippocampus and research showing that exercise has positive effects on the hippocampus and therefore memory, anyway, that's…

ANDI HORVATH

I knew it.



CASSANDRA WANNAN

But yeah, I think if we drill down a little bit, so again, once again, thinking about the hippocampus and some of the neurotransmitters in the hippocampus and there's this one called glutamate and there's this sort of hypothesis that people with schizophrenia have this abnormality of this particular neurotransmitter and people are actually developing drugs that sort of target this specific pathway. So if we can really drill down and sort of, you know, to a molecular level or to a neurotransmitter level, we might actually be able to come up with new treatments that will help people.



ANDI HORVATH
Tell me about how you go into this area. What inspired you?



CASSANDRA WANNAN
Well I did a psychology undergraduate and I never really had any clinical experience until my fourth year when I started honours. My supervisor was working with people with schizophrenia and I was lucky enough to get the opportunity to go to an inpatient facility and that was really my first time being able to interact with people who had the disorder. And it was really eye opening for me and I'd never really understood how much, not only the psychotic symptoms, but the cognitive symptoms really impacted on people's lives. I think that sort of catapulted me into really wanting to look at this further.



ANDI HORVATH
What misconceptions do people have about schizophrenia?

CASSANDRA WANNAN
There are a lot. I've met people who definitely have been a bit sort of cynical of the amount of time that we spend studying schizophrenia and a lot of it is based on misconceptions that people bring it on themselves by taking drugs, for example and you know, that's something that kind of frustrates me a little bit as a researcher.



ANDI HORVATH
Because it's certainly not drug induced all the time.

CASSANDRA WANNAN

No and of course there are, you know, there are cases of drug induced psychosis, but for most people with schizophrenia, there's a genetic component, there might be some sort of environmental component, I mean no one really 100 per cent knows what causes schizophrenia. We know that there's genes, we know that there's environment.



ANDI HORVATH

As a researcher, can you share with us some advice that you've already started to integrate from your elders, let's say, about how to be a good researcher, how to be a good expert?

CASSANDRA WANNAN
One thing is someone in my lab who I very much look up to pretty much told me to take every opportunity that you can, especially opportunities to network with other people and this is how you really bring about great research collaborations. I was lucky enough to meet someone after a talk one day and got talking to them about the work I was doing and the work they were doing and he said, “hey why don't you come to my lab and we'll teach you what we're doing with the hippocampus” and so I did and here I am with a published paper, a collaboration with another lab. I think that sort of thing is really important, being able to network with other people, make these collaborations, it's going to make your research so much better.

ANDI HORVATH

Be open to happenstance.

CASSANDRA WANNAN

Absolutely, yes.



ANDI HORVATH
And luck.

CASSANDRA WANNAN
Yes, yeah, well luck definitely plays into it but I think you really have to sort of take that first step to talk to someone. If you're at a conference and you go to a talk and you think, hey that's really great, that's really applicable to what I'm doing, go and talk to that person. Everyone loves talking about what they do in research and that's something I really discovered. So if you have the opportunity to meet someone that's working on something you're really interested in, just go up and say hi, go and talk to them.

ANDI HORVATH
You're at the pointy end of your PhD, which means you'll be writing up soon.

CASSANDRA WANNAN
Yes.



ANDI HORVATH

There will be the constant old chestnut question, how's the thesis going. How are you going to respond to that?



CASSANDRA WANNAN
Usually I cry for about eight or nine minutes when someone asks me how's my thesis going and then I sort of pull myself together and then I say, “yeah you know what, it's going okay.” I think that is the question that literally everyone asks you when you say you're doing a PhD, “oh how's it going, how far through are you” and I say, “you know what, it's not going too bad, I've got two chapters published, I'm working on my final one, so the pieces are slowly coming together” which is really nice.



ANDI HORVATH

Have you got time to even think about future you?

CASSANDRA WANNAN
A little bit, yeah. I'm sort of thinking about postdocs at the moment. I did have an offer of a postdoc in Montreal, which is pretty cool, but I also just had a baby, so that's kind of put a little bit of a spanner in the works. So I'm sort of figuring out where I'm going to be going from here, but yeah, I think a postdoc is definitely what I'll be looking at doing.

ANDI HORVATH
Next time we encounter people with schizophrenia, what would you like us to think?

CASSANDRA WANNAN
When you see someone with schizophrenia, it's important to think about how far we've come in the last 100 years. So you know, 100 years ago people with schizophrenia might have been locked up in an institution, things were pretty terrible…

ANDI HORVATH
Yeah, it was not good.

CASSANDRA WANNAN

No, it wasn't good. Today we have much better treatments, we have a much better understanding of what's going on in the brains of people with schizophrenia. We also have really great programs that are potentially stopping people from really progressing so far into the illness. So one great thing that's been happening is really early identification of the illness and once you get in there and start treating people really early, it seems to be that you can either halt them from transitioning to full psychosis, which is obviously a great thing, or you can sort of ameliorate the effects of the disorder a little bit, so that's a really great achievement I think.



ANDI HORVATH
Of course in the future their memories will be better.

CASSANDRA WANNAN
Exactly, yes.

ANDI HORVATH

Which I wouldn't mind if my memory was a bit better.

CASSANDRA WANNAN
Yeah, I mean we're certainly working on cognitive remediation for people with schizophrenia, so people are developing programs all the time that help people with their memory, their planning, things like that.



ANDI HORVATH

If I come and be your PhD student, can I examine the brains of people with schizophrenia to people with dementia and Alzheimer's? Is that a good project?



CASSANDRA WANNAN
Yeah, that's pretty cool. I mean there's a lot of overlap in some of the research areas, especially with the memory deficits in schizophrenia and I know I've certainly referred to a lot of the Alzheimer's literature when I've been looking at the hippocampus and memory functioning in schizophrenia. So yeah, I think that would be a great way forward.

ANDI HORVATH
Cassie Wannan, thank you.

CASSANDRA WANNAN
Thank you for having me.

CHRIS HATZIS
Thank you to Cassandra Wannan, PhD student at the Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne. And thanks to our reporter Dr Andi Horvath.

Eavesdrop on Experts - stories of inspiration and insights - was made possible by the University of Melbourne. This episode was recorded on July 23, 2019. You’ll find a full transcript on the Pursuit website. Audio engineering by me, Chris Hatzis. Co-production - Silvi Vann-Wall and Dr Andi Horvath. Eavesdrop on Experts is licensed under Creative Commons, Copyright 2019, The University of Melbourne. If you enjoyed this episode, drop us a review on Apple Podcasts and check out the rest of the Eavesdrop episodes in our archive. I’m Chris Hatzis, producer and editor. Join us again next time for another Eavesdrop on Experts.