RESEARCH HIGHLIGHTS AN INTERVIEW WITH…
The Kavli prize winners
Brenda Milner, Montreal Neurological Institute
What was it that sparked your interest in psychology and encouraged you to pursue research in this field? In 1936, I went to Cambridge University to study mathematics but soon realized that I would never distinguish myself in that field. I thought of switching to philosophy because I was still attracted to the study of logic but my colleagues advised me to try experimental psychology instead, since it would be easier to find a job afterwards. It turned out to be a very good choice. You are well known for your studies of patients with memory impairments following temporal lobe surgery for epilepsy, notably Henry Molaison (patient H.M.). What motivated you to study these patients? In 1950, I was working towards my Ph.D. in psychology with Donald Hebb at McGill University. Hebb had been invited by the neurosurgeon Wilder Penfield to send one graduate student to the Montreal Neurological Institute to study the patients undergoing a brain operation for relief of epilepsy. At the time, I was mainly interested in visual perception but, since the patients frequently complained of trouble with memory, I switched the focus of my research to memory disorders. My work has always been primarily motivated by intellectual curiosity, although I am of course pleased if the results prove to have practical applications.
What were the most important findings to emerge from these studies and how have they influenced the field? The most important findings to emerge were the importance of the medial temporal lobe structures (and particularly the hippocampus) in memory processes and the complementary effects of left and right temporal lobe lesions on different aspects of memory. The extensive work with William Scoville’s amnesic patient H.M. has continued to arouse great interest because people are now living longer and memory impairment of this kind is a common finding as age progresses. You have also conducted extensive work in patients with frontal lobe lesions. What were the key findings from these studies and how did they advance our understanding of the function of the frontal lobes? During the early 1950s, I also had the opportunity to study patients undergoing left or right frontal lobe removals for epilepsy. These patients were unimpaired on most memory tasks, but they showed a selective impairment in memory for the temporal order of recent events. This work was important in demonstrating highly specific deficits in the context of normal functioning on many memory tasks. How has the development of neuroimaging techniques influenced your research? Functional neuroimaging allows one to study the healthy human brain in action during the performance of different cognitive tasks, thus complementing and extending what we have learned from studying the behavioural effects of specific brain lesions.
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What do you think should be the top priorities for cognitive neuroscience research? What are the main obstacles to progress in this field that need to be overcome? I think that the top priority should always be basic research and that the practical applications, in the clinic and elsewhere, should follow from that. However, a major obstacle is our dependence on extensive technology to answer these basic questions, so that we will have to continue to convince the public of the value of such research. A further and quite different challenge is the need to bring molecular neuroscience and cognitive neuroscience into the same universe of discourse. John O’Keefe
The biennial Kavli prize in neuroscience has been awarded this year to Brenda Milner, Professor in the Department of Neurology and Neurosurgery at McGill University and Professor of Psychology at the Montreal Neurological Institute, Canada; John O’Keefe, Professor of Cognitive Neuroscience in the Department of Cell and Developmental Biology at University College London and Inaugural Director of the Sainsbury Wellcome Centre, London, UK; and Marcus Raichle, Professor of Radiology, Neurology, Anatomy and Neurobiology at the Washington University School of Medicine in St. Louis, USA. This year’s winners are recognized for the “discovery of specialized brain networks for memory and cognition”. In an interview with Darran Yates, the laureates reflected on their careers.
John O’Keefe, University College London
What inspired you to study neuroscience and how did you become interested in the hippocampus? After a classics education in high school, I switched to engineering. It was the era of Sputnik and I studied aeronautical engineering at New York University (NYU) in the evening while working full-time at Grumman Aircraft on Long Island, making airplanes and preparing for a glamorous career in the aerospace industry. It was not to be. At NYU, I used to moonlight from my maths and physics studies and audited philosophy courses — in particular, those in the philosophy of mind. I began to consider how the study of the brain might help to explain some of the classical problems of philosophy, such as the mind–body problem and consciousness, and more generally problems in epistemology, such as how we represent the external world. When the opportunity arose in 1960, I gave up my job and I went full-time at City College of New York. There, I came under two important influences — two influential teachers, Phil Ziegler and Danny Lehrman, who were both interested in the brain basis of bird behaviour VOLUME 15 | O CTOBER 2014 | 633
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RESEARCH HIGHLIGHTS and taught me the rudiments of research — and I came across Hebb’s ‘Organisation of Behaviour’, which really got me excited about the possibilities of understanding mind and behaviour in terms of brain function. I was then very fortunate to get a graduate place in Hebb’s Psychology Department at McGill University, one of the most important centres for what was then called ‘physiological psychology’. The term ‘neuroscience’ had not yet been invented. While I worked for my Ph.D. on the amygdala under Ron Melzack, many of my fellow students studied the effects of hippocampal lesions on rodent behaviour. They and I were convinced by Brenda Milner’s study of H.M. that the hippocampus had an important function in memory formation and storage, but it was proving very difficult to produce an animal model of the memory deficits he suffered from. When I decided to return to the study of the limbic system after my postdoctoral fellowship at University College London (UCL), it seemed like a part of the brain that would reward further study.
One day it dawned on me in a flash that the important correlate was the animal’s place in the environment How did you discover place cells? For my Ph.D. work on the amygdala and subsequent postdoctoral work with Pat Wall at UCL, I developed techniques for recording single units in behaving animals. When I shifted my attention to the rodent hippocampus in the early 1970s, I adopted a similar neuroethological approach. With my student Jonathan Dostrovsky, I monitored the activity of single hippocampal cells during different natural and learned behaviours. It was only after many months of looking at animals and listening to cells that I began to realize that the major correlate was not what the animal was doing, whether eating, exploring objects or carrying out simple lever-pressing tasks, but something about where it was doing them. One day it dawned on me in a flash that the important correlate was the animal’s place in the environment and that must be what the cells were coding for. That was a rather thrilling moment. You proposed that the hippocampus functions as a cognitive map. Could you briefly outline this concept and comment on how it has been received? The existence of place cells suggested that the hippocampus might function as a
cognitive map. The cognitive map idea was originally proposed by Tolman as a vague hypothetical construct to explain aspects of rodent behaviour, but it had fallen out of favour in psychology and was little discussed by the 1960s. Tolman had never considered the neural basis of the map idea, much less envisaging that it might be localized in a particular brain structure. My idea was that it consisted of a set of place representations connected together by a neural system representing the distances and directions between them. In a familiar environment, such a system would provide the animal with a flexible means of getting from its current location to other desirable places such as food locations and of avoiding undesirable locations such as those containing threats. The idea of the cognitive map, its location in the hippocampal formation and the effects of damage to it on the animal’s behaviour were subsequently spelt out in extenso in a book with Lynn Nadel published by Oxford University Press in 1978. The theory initially met with considerable resistance but over the years has enjoyed strong experimental verification and is now widely accepted. It predicted the existence of signals in the hippocampal formation representing distance and direction, and head direction cells have been found by Ranck, Taube and Muller in the presubiculum, while entorhinal grid cells, which may be signalling distance travelled in a particular direction, have been described in the Moser lab. The theory also predicted a selective deficit in spatial navigation following hippocampal damage and, together with Richard Morris, we confirmed this using the water maze task developed by him to test this idea. More recently, the postulated extension of the theory to the spatial and episodic memory functions of the human hippocampus has been verified by Neil Burgess and Eleanor Maguire. Aside from your discovery of place cells, what do you consider to be your other important findings? I believe that my Ph.D. research showing that cells in the amygdala respond selectively to specific objects of ethological significance and act as a short-term memory store for such information is important. In unpublished work, I have recently replicated this finding in rats and have found cells responding to such ethological stimuli as other rats or particular foods, and that many of these cells continue to fire for long periods of time after the cessation of the stimulating event. In the early 1990s, Michael Recce and I made another important finding: phase precession in hippocampal place cells. In
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phase precession, the phase of firing of each CA1 pyramidal cell shifts in a systematic way relative to the concurrent 8 Hz theta local field potential oscillation as the animal runs through the place field, and the phase correlates with the animal’s location in the field. It provides strong evidence that the hippocampus uses a temporal code and a rate code to represent aspects of the environment and is still some of the best evidence for temporal coding in cortical structures. Phase precession also pointed to an important role for the theta clock in the spatial functioning of the hippocampus. What practical implications do you foresee your work to have for the treatment of patients with memory disorders? Our understanding of hippocampus function at the network level will allow us to address the neural basis of neurodegenerative and psychiatric brain diseases. One approach is to create mouse models of diseases such as Alzheimer’s disease and ask how place cells and other aspects of hippocampal physiology become dysfunctional during disease progression. We already know from work with Francesca Cacucci and Tom Wills that place cells are less able to identify the animal’s current location in these mice and that this functional loss correlates with the animal’s inability on spatial memory tasks and its increased amyloid plaque burden. In another approach, Neil Burgess and Dennis Chan are developing sensitive spatial tasks modelled on the animal work for early diagnosis of dementia. What area of (neuro)science would you choose to pursue if you were currently at the beginning of your career? I have always been and continue to be an active bench scientist. I am still fascinated by the role of cortical networks in representing the environment and their relationship to consciousness. We won’t really have an adequate theory of the brain until we can account for this. With the advent of new techniques for simultaneously recording from large numbers of anatomically and genetically identified neurons coupled with virtual reality environments, we are beginning to get insights into the functioning of these neural networks. I want to continue to be part of this exciting research effort and would choose to do so if I were starting all over. More recently, I have renewed my interest in the social brain and in particular the functions of the amygdala. I believe that the concentration on the role of the amygdala in fear and anxiety has deflected our attention www.nature.com/reviews/neuro
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from its equally important role in areas such as the identification of conspecifics and the attribution of valence to foods and other rewarding aspects of the environment. Over the next years, I expect to spend a good proportion of my experimental endeavours in studying these systems.
Marcus Raichle, Washington Univeristy School of Medicine in St. Louis
You have made important contributions to the development and application of neuroimaging techniques, but what ignited your interest in the brain? The neuroanatomy and neurophysiology course I attended in my first year of medical school at the University of Washington was transformative. This conjoint course was taught by a truly distinguished faculty who seemed to enjoy teaching as much as I enjoyed learning. A weekly highlight of the course was the hour spent with the Head of Neurology, Fred Plum, discussing clinical– pathological correlations. I went on to have a very successful rotation on his service in my third year and I accompanied him to Cornell University Medical College in my senior year when he moved there to assume the Chair of Neurology. I subsequently trained in neurology with Fred Plum and other members of the Cornell faculty who were critical mentors in the clinic and the laboratory. How did you contribute to the development of positron emission tomography (PET) for the study of brain function? Some background is necessary here. In 1971, I joined the laboratory of Michel Ter-Pogossian at Washington University. Ter-Pogossian was a physicist who had pioneered the idea of using cyclotron-produced, short-lived, positron-emitting radionuclides in biology and medicine. The laboratory consisted of engineers, computer scientists and hot-atom chemists. I was the lone neuroscientist. I joined the Ter-Pogossian laboratory because of the prospect of doing regional measurements of brain oxygen consumption in humans, something that had not been previously undertaken. This, of course, was before the invention of X-ray computed tomography and the imaging techniques
that followed (that is, PET and MRI). Radiopharmaceuticals, therefore, had to be injected into the carotid artery and their fate had to be monitored by radiation detectors arrayed about the head in a helmet-like fashion. Although the techniques we developed were quantitative and conceptually elegant, they were limited in their use to patients undergoing carotid artery catheterization and non-human primates. All of that changed when, about 18 months after my arrival in St. Louis, Godfrey Hounsfield announced the invention of X-ray computed tomography, or the CT scanner as we know it today. My role in the physics, engineering and computer science of PET was very limited but I was privileged to have a ring side seat as I watched the first scanners being built. It was the physicists, engineers and computer scientists in the group who realized that it was possible to detect in three dimensions and quantitate emissions from radiopharmaceuticals labelled with positron-emitting radionuclides. They had come up with a way to do in vivo quantitative tissue autoradiography non-invasively. My primary role emerged from the need to devise and implement measurement strategies that could cull from data emerging from PET quantitative measurements of such things as blood flow, blood volume, oxygen consumption, receptor pharmacology and the like. I was in my element. Most of our work for the remainder of the 1970s consisted of developing, implementing and validating tracer-kinetic models, which were used to extract information from the PET data we were collecting. In the 1980s, we turned our attention to the relationship between local changes in blood flow and brain function. This remarkable relationship had been observed as early as the late 1800s. Again, methods were of paramount importance. Over the course of several years we developed a means of image registration and normalization (that is, registering the brain anatomy of individuals to a standard template brain) that made image averaging across subjects feasible for the first time. We borrowed stereotaxy from neurosurgery and radiology to help to pinpoint the location of blood flow responses in the brain. Finally, through a gift from the late James S. McDonnell, we were fortunate to hire Michael Posner, one of the world’s leading cognitive psychologists. Together, we were able to combine our imaging techniques with sophisticated behavioural tasks, and this approach culminated in a paper in Nature entitled “Positron emission tomographic
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studies of the cortical anatomy of single-word processing”, which became the experimental prototype for the then-emerging field of cognitive neuroscience. What questions did you investigate using PET and what were your main findings from these studies? It’s difficult to summarize 42 years of work in a single paragraph as we continue to use PET for its unique capacity to measure brain metabolism quantitatively, despite the ascendance of functional MRI (fMRI) for brain mapping. A wide range of subjects have been tackled with PET by our group and a select group of other investigators in the world who are lucky enough to have the extensive infrastructure needed for such work. These ranged from studies of language, emotion and memory in the cerebral cortex to the first studies of the role of the cerebellum in cognition. We have been very active in studies of brain metabolism, particularly the role of glucose in biosynthesis related to development, learning and memory, and disease. What developments and findings in neuroscience (including your own) enabled the development of fMRI? fMRI is dependent on local changes in haemoglobin oxygenation that accompany changes in brain activity. These changes in haemoglobin oxygenation result from the fact that changes in blood flow that accompany changes in brain activity are greater than those occurring in brain oxygen consumption (that is, the supply of oxygen increases more than the demand for it). This fact, which we documented in two papers in 1986 and 1988, provided a physiological rationale for the later development of fMRI. It was the work of Siegi Ogawa at the Bell Laboratories who demonstrated directly that changes in blood oxygenation could be detected by MRI. From his observations, he coined the term bloodoxygen-level-dependent (BOLD) contrast. The first studies of BOLD contrast in humans were published almost simultaneously in 1992 by four groups all citing our physiological observations as the basis for their fMRI mapping techniques. Could you describe your seminal studies on intrinsic brain activity and the default-mode network? Intrinsic brain activity caught our attention for two reasons. First, intrinsic activity incurs a far greater cost to the brain in terms of energy consumption than evoked activity. The second reason was the serendipitous VOLUME 15 | O CTOBER 2014 | 635
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RESEARCH HIGHLIGHTS observation that intrinsic activity was remarkably well organized. This latter fact came to our attention when we observed, in addition to the usual task-relevant increases, activity decreases when we compared scans performed during tasks with those performed when subjects were resting quietly but awake in the scanner. What was remarkable about these decreases was their spatial consistency across a wide range of tasks. The areas involved were the medial surfaces of the parietal, prefrontal and temporal cortices, and the lateral surfaces of the temporal and parietal cortices. In pursuing this observation through PET metabolism studies, we were able to show that this remarkable set of areas was not activated in a conventional sense during quiet repose. Rather, as we suggested in the
title of our paper, these areas represented “a default mode of brain function”. This group of areas has become known as the brain’s default mode network and has emerged as a critical component of the brain’s functional infrastructure. Interestingly, elements of this network are present in non-human primates and rodents. How has the assessment of intrinsic brain activity influenced how we understand various brain diseases? The impact of studies of intrinsic activity on our understanding of various brain diseases is only just beginning to be felt. This parallels our understanding of intrinsic activity itself, which has gone from a surprising realization of its potential importance to remarkable evidence of its
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organization. But we have only begun to tap the wealth of information potentially available in the ongoing rhythms of the brain from the spontaneous fluctuations in the fMRI BOLD signal to fluctuations in electrical activity and in the metabolic state of cells. It is our increasing ability to tap into the richness of this information that portends significant advances in our understanding of human behaviours at an ever more sophisticated level. FURTHER INFORMATION The Kavli Prize: http://www.kavliprize.no Brenda Milner’s homepage: http://www.mni.mcgill.ca/ neuro_team/cognitive_neuro/brenda_milner John O’Keefe’s hompage: http://www.ucl.ac.uk/cdb/ research/okeefe Marcus Raichle’s homepage: http://www.nil.wustl.edu/labs/ raichle/
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