Nobel Prize Laureate Prof. O’Keefe: Spatial Memory Tests Can Help Identify Early Patients at Risk of Alzheimer’s Disease

To begin to understand things like thinking and particularly consciousness is the Holy Grail for most brain researchers, Nobel Prize winner John O’Keefe said in a BTA interview. The American-British neuroscientist and psychologist shared the Nobel Prize in Physiology or Medicine in 2014, together with May-Britt Moser and Edvard Moser, for discovering “place cells” which form a person’s navigation system in the brain.

Prof. O’Keefe was among tens of Nobel Prize laureates who met in Lindau, Germany in late June for the 72nd edition of the traditional Lindau Nobel Laureate Meetings.

In his presentation in Lindau, he briefly recounted his professional journey: often at a crossroads and having to make a choice of which direction to take, he says, making a parallel with his discovery, the hippocampal navigation system. The American-born researcher, who has lived and worked at University College London in the UK for decades, attended a classical school but, he said, failed to learn Latin and remembered almost nothing of the history of ancient Greece. He went to university to study engineering, but gradually realized that he was more interested in psychology and philosophy and often asked himself questions about the workings of the brain. Thus, he found himself at a crossroads: to finish his education and become an aerospace engineer or seek ways to study the brain. He chose the second path and enrolled at City College of New York.

At the time, there was no major in neurobiology, so I went through every possible course, said the researcher. After completing his bachelor’s degree at the New York college, he went to Canada, where he graduated as a master’s student and subsequently as a doctor of psychology at McGill University. There, in his first year, he began working with veteran neuropsychologist Brenda Milner.

His work in the late 1960s on the responses of mouse brains to environmental stimuli drew criticism from his colleagues. I said to myself, let’s forget what we are interested in, let’s see what’s interesting for cells, let’s see how cells behave in the normal everyday life of the rat. Everybody working in physiology said we were crazy, O’Keefe said in his lecture. However, he discovered cells in the hippocampus that are triggered when the animal finds itself in a certain place and then proved that these cells create memories of certain places and thus help with spatial orientation. Among the latest discoveries of Prof. O’Keefe and his team, after numerous experiments, is that cells in the hippocampus create a vector field directed towards a target location. This is refining the understanding of the brain’s navigation system located in the hippocampus.

Prof. O’Keefe talked to BTA special correspondent Antoaneta Markova in Lindau about the progress in the study of this navigation system, the practical application of his scientific discoveries of recent decades, and understanding thinking and consciousness.

What is the next step in your research – is it about the navigation system of the hippocampus or something else?

That’s a good question. As you know, we’ve been studying the area of the brain, the hippocampus, for some time – many years now, and we believe its primary function is to provide information about where the animal is and where things are located in space and how to get from one to the other. So it provides not only a spatial memory system, for what you experienced in particular locations, but how to go from one place to the other, and we’ve recently discovered how that part of the brain, the hippocampus, actually does it – by creating a signal which actually points in the direction of where you want to go.

So we’re quite pleased with that. And we’re now thinking we need to go the next step. And the next step is something that we’ve been thinking about for a long time and comes from human patient research. We know that patients with damage in this part of the brain, the hippocampus, not only have trouble navigating but also have trouble remembering about events of the past that they have personally experienced. These are called episodic memories. And to have an episodic memory, you need to not only know where you were in the past and when you experienced an event, for example where you had lunch yesterday and who you were were with, but you have to know that it was yesterday and not the day before or the day before that. So you need to have some sense of linear time. You need to know not only where you experienced something, but when you experienced it.

And there are some hints from our colleagues that some of the cells in the hippocampus and areas related to hippocampus are actually providing something like a time signal. And so we’re very interested in whether that occurs. We’re sure it must occur in human beings because they show us that they have this kind of ability. But we’re interested in whether an animal such as the rat also has this ability. And for a long time we couldn’t understand why a rat might want to do this, why would a rat want to know what it did yesterday? And we are now beginning to think it has something to do with foraging when animals go to a particular location looking for food, get through there and then go away. And then they have to know how long ago it’s been since they’ve been there in order to calculate whether that’s a good place to go back to. They have to have some sort of a time signal. So we’re interested in finding out what that that time signal looks like. We’re doing experiments on that as are people in other laboratories. And we have a fairly good idea what kind of characteristics that time signal has to be. It can’t just be something which says I did something 2 seconds ago or 5 minutes ago. It has to be something which is good for a couple of days or even weeks and it has to be able to tell when we did something – was it a very long time ago or just a short period of time. So we have an idea of what kind of structure the signal has to have, but we haven’t seen them yet. So we’re doing experiments now on those sorts of questions.

What is the most interesting thing for you in the human brain, what would you like to know about it?

I think the Holy Grail for most brain researchers and certainly speaking for myself would be to begin to understand things like thinking and particularly consciousness. There’s a great gap in our understanding of the brain as a material organ. An organ that is much more complicated, but it has many of the same properties and it depends on the same material as the liver or the heart or any of these other biological organs. And when we think about consciousness – and philosophers have thought about this for many centuries and millennia, it feels like something very, very different. It feels like it’s an immaterial substance. And so we have great difficulty thinking about how something as physical as the brain with all its neurons and their interconnections and the way they operate in time and talk to each other with action potentials, but how that gives rise to something which we experience and we all believe what we possess, which is consciousness.

So I think one of the great frontiers in brain research would be to try to understand this and it’s not that people haven’t tried to understand it, but to try to understand how you solve this very deep philosophical problem of how you can have an interface between mind and matter, or how in much more concrete terms the brain gives rise to these internal impressions, internal thoughts and internal experiences. And we still are not sure which parts of the brain are involved and how much there is localization, or whether it’s the whole brain operating together. It certainly looks as though consciousness is something which brings together many of the different functions of the brain. When I look out at the world, I see very complex, multidimensional sights, sounds, the highly structured environment we’re sitting in a space and we’re still struggling to see how all of that can be put together in the brain. Because we know that the parts of the brain which enable you to see things are different from and located in different places from the parts of the brain that are enabling you to hear things and so on forth. So there’s some process going on the brain which brings all this together or allows all of these very disparate parts of the brain to communicate with each other and create this integrated picture that we have of the world. Where not only do we have a spatial framework in which we exist, but we know that there are other people and we have feelings and emotions and we hear things and we interpret them as thoughts and language and things like that. So I think this is a very hard problem. It’s actually called “the hard problem” by philosophers and it is something that we have not made too much progress towards. We’ve made a lot of progress in understanding a lot of the functions of the brain, but that’s one of the areas which actually, for a long time, people said we shouldn’t even go there. We shouldn’t ask these questions and in fact the great French philosopher Descartes was the first one who said “let’s just try to understand the parts of the brain that are mechanical. And let’s leave that really hard problem aside”. But I think we’re now at the point where we have to face up to this hard problem, which we’ve been avoiding for about 400 years.

So generally speaking, how much do we know about the human brain? Is it enough?

I think in terms of answering that question that we have some insight into which part to look if things go wrong in some parts of the brain and we are faced with patients who are unconscious.

It doesn’t help us too much. We’re still struggling with the idea are some parts of the brain involved in consciousness and others aren’t? Is there any localization? Is it the whole brain? So I have thoughts about it, but I think the best way of thinking about it is we’re still not sure we know answers to very simple questions like where is consciousness located, is it localized or is it distributed around the whole brain? Is it a function of the whole brain or of specific parts of the brain? We’ve made enormous progress in brain research. We know a lot about the different aspects of the brain. And we even know enough now, so I think we can begin to think about ways in which our knowledge will help us to address some of the major neurological problems that we have in society.

I myself realized some time ago – it was well over 10 years ago, in a conversation with one of my former students who’s a neurologist now, that we probably knew enough about these areas of the brain I’ve been working on – the spatial areas of the brain, the hippocampus and the entorhinal cortex, which turned out – and we had no inkling of this when we first started working on them, to be the areas of the brain which are first attacked by the toxic mechanisms in Alzheimer’s dementia. So thinking about that and talking to my former student, we said, OK, maybe it’s time to see if we can use this knowledge which was gained purely for pure research. We were just trying to understand how these parts of the brain work and now that we think we know enough about how they work let’s apply this knowledge to a particular problem- in this case, Alzheimer’s disease.

So we are doing things like creating genetically-modified animals where we put the genes into them which we think at least create some types of  Alzheimer’s disease – the genes which we know from familial Alzheimer’s disease lead to the types of brain changes that we see in Alzheimer’s. And we can create models where we put these genes into the genome of these animals and they have some of the signs of Alzheimer’s disease. And then we can go and look at the cells that we know how they work normally and see how they’re beginning to be affected by the effect of that gene and how they begin to fail.

We and other groups have done that. So you can look at, for example, the cells in the hippocampus which in the normal animal have what we call place fields and they identify a particular part of space.

When we look at these animals, what we see is they begin to fail and the area of space that they identify is much wider and much less clear. So we’re beginning to see how the cells fail and what we would like to see then is how these malignant toxic proteins begin to move in the brain, how they affect the areas like the hippocampus and how they move from there into other areas in the brain. We’re also using our knowledge that we gained, again purely because we were interested in learning about spatial memory, to try to test the earliest signs of Alzheimer’s disease in humans. So for example, we believe that, like rats, humans also use these parts of the brain to find their way around. And so we are developing very sophisticated spatial tests and we use, for example virtual reality navigation to develop these tests. And then we use these tests to see if we can test and identify people at the earliest stages of Alzheimer’s, and we’ve done that successfully. We can use that and look at what biomarkers and other aspects change in these patients. So we’re very optimistic that we will be able to develop tests which will enable us to identify some of the earliest stages in people who are at risk of these diseases, because of course, if we ever have a cure or a drug, we’re going to need to give it to people before they get the disease and we don’t want to give it to everybody. So we need to have techniques to identify these people. We can do it by looking at blood biomarkers and these spatial memory tests which we think will be very, very useful for doing that.