Mapping memories: Eleanor Maguire and brain imaging
"If any one faculty of our nature may be called more wonderful than the rest, I do think it is memory. There seems something more speakingly incomprehensible in the powers, the failures, the inequalities of memory, than in any other of our intelligences. The memory is sometimes so retentive, so serviceable, so obedient; at others, so bewildered and so weak; and at others again, so tyrannic, so beyond control! We are, to be sure, a miracle every way; but our powers of recollecting and of forgetting do seem peculiarly past finding out." - Jane Austen, 'Mansfield Park'
The way that our recollections shape who we are and the way we think has long been explored in literature and popular culture, from the writings of Marcel Proust and Philip K Dick to films such as 'Strange Days', 'Memento' and 'Eternal Sunshine of the Spotless Mind'. But when Eleanor Maguire first became interested in the subject, her motivation to put memory on a scientific basis was more personal. "I am absolutely appalling at finding my way around," she confesses. "I wondered: 'How are some people so good and I am so terrible?'"
She started out her quest to understand memory while working with patients for a doctorate at University College Dublin. Today she is still dedicated to the quest, as a Wellcome Trust Senior Research Fellow and Professor of Cognitive Neuroscience at the Wellcome Trust Centre for Neuroimaging at University College London, where she heads the Memory and Space research laboratory.
Maguire wanted to explore how our experiences, both big and humdrum, forge and sunder the vast network of connections between cells in a human brain: it is these connections that are central to who we are. And the spur that drives her on to understand them remains the same now as it was when she began her great scientific adventure in Dublin: "I still get lost in the Centre for Neuroimaging and I have been working here for 15 years."
She and her dedicated team of half a dozen colleagues are studying these gossamer threads of recollection with brain scanners, notably magnetic resonance imaging (MRI) techniques. Some are tuned to reveal the extraordinary structural complexity of the brain (structural MRI), others to the tiny changes in blood flow that accompany thought (functional MRI, or fMRI).
But central to her work is the field of neuropsychology, working with people who have some kind of memory impairment such as amnesia. "fMRI can tell you which brain areas are involved in memory but you are never sure which ones are really necessary. That is where the study of patients comes in."
She is most fascinated by one region located deep in the brain called the hippocampus, so named because the Venetian anatomist Julius Caesar Aranzi (in 1587) initially likened it to a seahorse ('hippocampus' in Latin). This is known to be a memory centre - and is damaged in people with amnesia - but Maguire's investigations suggest that its role is more subtle and interesting.
She believes (as do others) that it provides a kind of spatial scaffold for memories, one that is essential if we are to make sense of our experiences. "One patient with amnesia tried to articulate what it was like never being able to remember. He said: 'It's like having a load of clothes I need to hang up in a wardrobe but there's nothing to hang them on, so they all fall on the floor in a mess'."
In the long run, the hope is that Maguire's research will help us understand how memories can be affected by age and shredded by dementia and developmental disorders. With that understanding may, of course, come new tests and treatments. "We are all about helping patients, ultimately. But we can't come up with new kinds of rehabilitation until we understand precisely how memory works."
Learning 'the Knowledge'
Her first big advance came in 2000, in a study that would generate headlines worldwide, capture the public imagination and even win her a share of the highly coveted Ig Nobel Prize, a parody of the Nobel Prizes that is handed out each year for achievements that "first make people laugh, and then make them think". Even today, she still gets hundreds of media inquiries every year to find out more about this particular piece of research.
In her first experiment for this study she scanned the brains of 16 London black-cab drivers who had spent an average of three or four years learning 'the Knowledge' - the entire layout of the 25 000 streets in London. What she discovered challenged the prevailing view of the brain as at best static and at worst forever shedding cells as a result of knocks, hangovers and ageing. In fact, the brain behaves like a muscle: use brain regions and they grow.
What was remarkable was that she found the taxi drivers had a larger hippocampus than control subjects, particularly on the right side. The longer they had been on the job, the larger their hippocampus. These findings seem to indicate that the hippocampus plays an important role in storing spatial memories.
She moved on to study London bus drivers. It turns out that bus drivers do not have the same enlarged area, even though they had been carefully selected to have had similar experience on the road. This suggests that general skill at driving is not related to hippocampus size, and that the difference in size is indeed linked to knowledge of the layout of the city's streets built up by taxi drivers over many years, since bus drivers use much more restricted routes.
To make absolutely sure that the hippocampus is indeed central to navigation, Maguire and colleagues went on to follow the progress of trainee taxi drivers. As they became more experienced, she could peek at what was happening to their hippocampi. It turns out that only half pass their final test of the Knowledge. In a satisfying conclusion to her effort to pin down the role of the hippocampus, she found the successful drivers were the ones that showed the greatest alteration of the hippocampus. Essentially, "experience can change the brain," she says. There was a fascinating corollary to this: did the half who failed to qualify lack a hippocampus that was sufficiently malleable? "Perhaps there is a genetic disposition. We will have to look into this."
Studying the way the drivers used this enlarged area of the hippocampus was more difficult. Because an MRI scanner is a room-sized affair, where the subject lies inside a giant magnet, there's no way to carry out these studies in the back of a cab. Maguire and her team devised a series of virtual-reality tasks that the subject can carry out, without physically moving, on a screen inside a scanner. Developing these virtual-reality environments was not easy, even though they adapted versions of commercially available video games. "We had to take out all the shooting and monsters so that we were left with the basic environment."
Using the PlayStation 2 video game 'The Getaway', which is set in central London, she and her researchers could examine how taxi drivers use their hippocampi and other brain areas when they navigate around the city. They found that the hippocampus is most active when the drivers first think about their route and plan ahead. By contrast, activity in a diverse network of other brain areas changes as they encounter roadblocks, spot expected landmarks, look at the view and worry about the thoughts of their customers and other drivers.
Inside the hippocampus and neighbouring brain areas, it seems that three basic types of cell are involved in spatial maps. These are called place cells, head direction cells and grid cells. Place cells map out our location, lighting up to say 'you are here' when we pass a specific place; there are thought to be hundreds of thousands of these cells in the hippocampus, each preferring a slightly different geographical place. Head direction cells act like a compass, telling us which way we are facing. And grid cells tell us how far we have travelled, akin to how we use latitude and longitude for navigation.
Maguire's team has done further work on black-cab drivers to see whether the hippocampus will shrink back to its normal shape if they stop using it 'professionally'. After the difficult job of tracking down retired cabbies ("they are so hard to find," she explains, "because they never seem to retire") she found that, yes, this was indeed the case.
To complement this finding, she studied a taxi driver of 40 years whose hippocampus had been damaged by a viral infection, leading to amnesia. While he was able to navigate using major or 'A' roads, he was no longer able to navigate through the winding, minor streets of the capital. "That shows that the hippocampus is necessary for fine detailed spatial representation of the city."
Do similar changes accompany other feats of exceptional memory? To find out, Maguire and colleagues studied participants in the World Memory Championships, which take place every year in London. "People entering the World Memory Championships can do amazing things," she explains. "They can memorise the order of cards in deck after deck of cards, for example. One memory champion passed time waiting in reception prior to his scan by memorising pages from the phone book - pretty well, too; I tested him on it."
What was fascinating was that she could find no structural changes of the kind seen in the taxi drivers. Like the bus drivers, it seems that their memory feats did not place the same demands on the hippocampus. This emerged when she asked them what strategies they used. Nine out of ten of them had used the same strategy: an ancient Greek method, called the method of loci. "It's based on navigation: they imagine going down a street they know well, place items at certain positions along the street, then mentally retrace their route to find the items."
Although this strategy uses spatial memory to boost performance, the amount of large-scale space memorised is small, possibly accounting for the lack of structural changes in the hippocampus. "Their brain doesn't have to change to accommodate a large map of London in their heads as it does for the cab drivers; the memory champions just need to memorise a couple of routes in detail."
She could also ask a more basic question. Does the hippocampus store a 'virtual map' of the physical world or is it recalling relationships between objects in a more generic way? To test this, the team used fMRI to reveal which parts of participants' brains were active as they visualised the spatial route between their friends' houses compared with the social connections between the friends themselves. The tasks activated separate brain networks: the hippocampus is active when people visualise navigating to different locations but not when they navigate social networks of friends. What is satisfying is that the conclusion of this work complements the findings of studies of rats: the hippocampus is central to navigation.
Remembering our past
In recent years, Maguire has focused more on the second critical role of the hippocampus, in laying down autobiographical (episodic) memories of our past experiences. Here, people with anterograde amnesia have played a central role in her studies.
These people live permanently in the present. Their speech and intellect tends to remain intact, because remembering facts and general knowledge is not dependent on the hippocampus. However, their experience of the world is frozen in time: they cannot remember anything that occurs after their brain damage took place. Maguire says: "If they do a couple of hours of tests with me, for example, and I leave the room for ten minutes and come back, they can't remember anything about me or what they had been doing. They can't live alone because they can't remember if they turned the gas off or paid their bills. Sometimes, which is very sad, if a spouse dies, they can't remember their loved one is now gone."
In the healthy brain, many regions are involved in supporting personal, autobiographical memories, because these are coloured with emotions and depend on the spatial, temporal and social context. To understand how the brain stores and recalls this form of memory, it is important to evoke the 'whole' memory during studies. One way of doing this is to project a photo of a party or wedding from a family album onto the screen, prompting the participant to recall and re-create this particular event in their past while their brain is being scanned.
In this way, Maguire and her team have investigated the episodic memories of everyday events, such as seeing someone posting a letter or preparing to ride a bike. To explore how such memories are recorded, her team showed ten volunteers three short films and asked them to memorise what they saw. The films were basic, sharing a number of similar features: all included a woman carrying out an everyday task in a typical urban street, and each film was the same length, seven seconds long. For example, one film showed a woman sipping coffee from a paper cup in the street before discarding the cup in a litter bin; another film showed another woman posting a letter.
The volunteers were then asked to recall each of the films in turn while inside an fMRI scanner. A computer program then studied the patterns and had to identify which film the volunteer was recalling purely by looking at the pattern of their brain activity. Remarkably, it was possible to tell which film they were recalling.
Although a network of brain areas support memory, the computer program performed best when analysing activity in the hippocampus itself, suggesting that this is the most important region for representing episodic memories. In particular, three areas of the hippocampus - the rear right, front left and front right areas - seemed to be involved consistently across all participants.
This work suggests that our memories are encoded within the brain in a predictable way. While earlier fMRI work has shown the typical brain areas involved, this study, after averaging the activity in many heads, showed the precise circuits used to lay down a recollection of one particular memory trace in an individual's brain, down to a resolution of just over one cubic millimetre - revealing much more detailed information about the hippocampus at work. "That is very exciting because it means we can look at specific memory traces," says Maguire.
Now it is possible to investigate precisely which brain areas hold a given memory, how this trace varies with time and what happens as a result of disease or injury. But, of course, there are even more speculative implications. Does this mean that we will one day be able to use a scanner to read a mind?
Maguire emphasises that her participants were tasked with recalling one of three short films that they had previously viewed, so the researchers were already aware of the nature of what it was they were thinking about, just not the identity. "There are ethical issues but we did do the study with the cooperation of the patients and, although arguably a form of mind reading, it does take place under very controlled circumstances."
While confirming the key role of the hippocampus in recalling past events, Maguire and colleagues went on to make a fascinating discovery when she asked people with amnesia to describe imaginary experiences. She and her team asked the patients to imagine and then describe in detail situations in commonplace settings, such as a beach, pub and forest, as well as potentially plausible future events such as a Christmas party. The patients' ability to construct future and fictitious events was also severely impaired. "The role played by the hippocampus in processing memory was far broader than merely reliving past experiences," she says. "It also seems to support the ability to imagine any kind of experience including possible future events. That is why, in this sense, people with damage to the hippocampus are forced to live in the present."
"Furthermore, the patients reported that they were unable to visualise the whole experience in their mind's eye, seeing instead just a collection of separate images. We believe this suggests a common mechanism that might underpin both recalling real memories and how we visualise imaginary and future experiences, with the hippocampus providing the spatial backdrop or context into which the details of our experiences are bound," she explains. The work closes the loop with her studies on spatial navigation, and other animal studies in the literature, showing that space may be the key to understanding the function of the hippocampus and its role in memory.
Maguire has come a long way since she first thought about the neuroscience of memory in Dublin. She has won much recognition of her extraordinary contribution: the Cognitive Neuroscience Society Young Investigator Award; two Wellcome Trust Senior Research Fellowships; the Royal Society Rosalind Franklin Award; and the Feldberg Foundation Prize, made for outstanding contributions to science.
But her quest is far from over. Huge challenges remain if she is to confirm that the hippocampus indeed plays a central role in providing the spatial context for our experiences and helping us to think about the future. "I believe that it is there to support coherent scenes. It is providing a spatial backdrop, or canvas, on which we play out the recall of memories, plan a route or simulate what will happen to us in the future. But that is still quite controversial and we need to link a lack of spatial representation directly to amnesia."
She is also keen to apply her work in novel treatments for memory disorders. The good news is that the study of taxi drivers suggests that it is possible to train a hippocampus. For people suffering from hippocampal damage, and associated difficulties with memory, the question of whether the brain can mend itself, and memory be recovered, is a pressing one.
"Findings like those from our study of London cab drivers show that structural changes can occur in healthy human brains. Perhaps in the future we could use that kind of understanding to help people with hippocampal damage." But, of course, many other circuits are involved in memory. "When we use fMRI, other brain regions are engaged also. We still don't know a great deal about what they are doing. Until we do, it won't be possible to design a memory rehabilitation programme with confidence."
Today, Maguire is gratified that her work has gone beyond the confines of the international conference circuit and academic journals. More than a decade after she started her pioneering research, she sometimes finds herself in the back of a London taxi. "Cabbies often tell me about my work, not realising who I am. It is extraordinary to hear them talk about the hippocampus."
Thanks to Maguire's pioneering work on memory, many London cab drivers now possess a little of neuroscience's equivalent of the Knowledge. For years to come, her work will be remembered for how it changed the way we think about memory.
Roger Highfield is the Editor of 'New Scientist'. For two decades he was the science editor of the 'Daily Telegraph' and he still contributes a column to the science page of the newspaper. He has written or coauthored several books. The latest, written with Martin Nowak, is 'SuperCooperators: The mathematics of evolution, altruism and human behaviour (Or, Why we need each other to succeed)'.
Top image: Eleanor Maguire. Credit: Wellcome Images
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