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Neuroimaging of Cognition: Past, Present, and Future

2008; Cell Press; Volume: 60; Issue: 3 Linguagem: Inglês

10.1016/j.neuron.2008.10.038

1097-4199

Raymond J. Dolan,

Psychosomatic Disorders and Their Treatments

Neuroimaging, particularly that based upon functional magnetic resonance (fMRI), has become a dominant tool in cognitive neuroscience. This review provides a personal and selective perspective on its past, present, and future. Two trends currently characterize the field that broadly reflect a pursuit of "where"- and "how"-type questions. The latter addresses basic mechanisms related to the expression of task-induced neural activity and is likely to be an increasingly important theme in the future. This trend entails an enhanced symbiosis among investigators pursuing similar questions in fields such as computational and theoretical neuroscience as well as through the detailed analysis of microcircuitry. Neuroimaging, particularly that based upon functional magnetic resonance (fMRI), has become a dominant tool in cognitive neuroscience. This review provides a personal and selective perspective on its past, present, and future. Two trends currently characterize the field that broadly reflect a pursuit of "where"- and "how"-type questions. The latter addresses basic mechanisms related to the expression of task-induced neural activity and is likely to be an increasingly important theme in the future. This trend entails an enhanced symbiosis among investigators pursuing similar questions in fields such as computational and theoretical neuroscience as well as through the detailed analysis of microcircuitry. In the late 1970s, I commenced training as a psychiatric resident at a large mental institution in North London's Friern Barnet Hospital, uncertain how my future would unfold. This crumbling Victorian institution, which gave rise to the cockney colloquialism for a madhouse, "Colney Hatch" was famously, and sympathetically, depicted in Richard Hunter's book "Psychiatry for the Poor" (Hunter and MacAlpine, 1973Hunter R.A. MacAlpine I. Psychiatry for the Poor: 1851 Colney Hatch Asylum—Friern Hospital 1973: A Medical and Social History. Dawsons of Pall Mall, Folkestone, England1973Google Scholar). The very same author, a maverick psychiatrist, used to conduct a weekly postmortem brain dissection demonstration on his deceased patients. At the time, within mainstream psychiatry, the mere idea of studying the human brain as a means to unravel the mysterious nature of psychiatric illness was viewed as arcane and treated with derision. Psychiatry was then a discipline paralyzed by a pervasive intellectual agnosia when challenged as to the likely causes of severe mental disorder. I found Hunter's weekly brain dissection demonstrations fascinating and frustrating. Although the patients coming to postmortem had suffered life-long severe mental illness, it was rare for us to detect any macroscopic pathology. Indeed, I cannot recall a single instance, despite the proselytizing zeal of our demonstrator, where a convincing clinicopathological correlation could be established. As part of the weekly ritual, and no doubt to reinforce our attendance, we were served tea and chocolate biscuits, which provided the context for idle conversation among my fellow psychiatric residents. We often, subversively given the context, speculated that the only conceivable avenue for progress was not through brain dissection, however fine grained, but by dint of some future technological innovation. What we often imagined was a dissecting device for the living, one that would enable the physiological function of the brain to be revealed in its entire splendor. Less than 30 years later, I need only to remind myself of this time period to fully appreciate the extraordinary advances that have ensued in the interim, developments that have delivered the sophisticated technology of functional brain imaging. By 1984, I had completed my first stint as a researcher, thanks to a generous training fellowship from the Wellcome Trust. At this time, there was growing excitement about a technology that seemed to presage a conversion of our postmortem dissection table fantasies into reality. A number of centers around the world were beginning to use positron emission tomography (PET) to measure regional cerebral metabolism using radiolabeled glucose or regional cerebral blood flow (rCBF) using radiolabeled oxygen. The scientific outputs from these centers were primarily resting-state investigations, where the emphasis was on physiological quantification of blood flow and metabolism. Yet, for those of us who took an interest, we could immediately intuit its future possibilities. Within the space of a few years, a number of these centers were extending resting-state applications of PET, capitalizing on the potential of perfusion techniques to measure task-induced brain activity. In hindsight, these techniques appear crude and unsophisticated, but at the time they were of enormous importance in realizing a dream within neuroscience, namely the prospect of a physiological window into the human mind. I am certain that the excitement and expectation generated by these developments was the principal motivating factor for the many young scientists who committed to the field and were happy to be labeled by their colleagues, often mockingly, as "imagers." The intellectual promise offered by what I perceived as a revolutionary means to study the brain was certainly sufficient motivation for me to return to research once I completed my psychiatric training. In 1989, I arrived at the MRC Cyclotron Unit at the Hammersmith Hospital in London where I and my close colleagues over the next 20 years, Karl Friston and Chris Frith, joined a team led by Richard Frackowiak. We committed, as did a number of other pioneering groups worldwide, most notably the group of Marcus Raichle in St Louis, to an ambitious program to use noninvasive imaging to map the functional architecture of the living human brain. What follows in this review is a highly selective perspective on how this field has evolved, its current and future directions. As a consequence, and because of a remit that includes a word restriction, the review makes no claim to comprehensiveness. To measure brain activity associated with discrete states of mind is the holy grail of cognitive neuroscience. In the late 1980s and early 1990s, there were two significant developments, resting on nascent progress in perfusion imaging, that proved pivotal in realizing this dream. The first was the development of sophisticated data analysis tools, subsequently becoming a standard in the field, which provided whole brain imaging analysis in the form of statistical parametric maps (Fox et al., 1988Fox P.T. Mintun M.A. Reiman E.M. Raichle M.E. Enhanced detection of focal brain responses using intersubject averaging and change-distribution analysis of subtracted PET images.J. Cereb. Blood Flow Metab. 1988; 8: 642-653Crossref PubMed Scopus (391) Google Scholar, Friston et al., 1991Friston K.J. Frith C.D. Liddle P.F. Frackowiak R.S. Comparing functional (PET) images: the assessment of significant change.J. Cereb. Blood Flow Metab. 1991; 11: 690-699Crossref PubMed Scopus (1459) Google Scholar). Second, the early 1990s saw the surprising and rapid emergence of a new approach to brain mapping using MRI based upon the blood-oxygen-level-dependent (BOLD) technique (Ogawa et al., 1990Ogawa S. Lee T.M. Kay A.R. Tank D.W. Brain magnetic resonance imaging with contrast dependent on blood oxygenation.Proc. Natl. Acad. Sci. USA. 1990; 87: 9868-9872Crossref PubMed Scopus (4243) Google Scholar). This latter approach had significant benefits over PET, including greater spatial resolution and the absence of the potential hazards associated with radioactive tracers. The significance of this development derives from the fact that neuroscience now had a technology that was noninvasive and that afforded multiple repeated measures of brain activity across various task manipulations. The end result was fMRI, a technique that afforded much greater experimental flexibility. Apart from obvious methodological advantages associated with fMRI, it had, in my view, an equally important cultural consequence. Access to PET as a technique, entailing by necessity the use of ionizing radiation, was vested in the hands of an elite. Their privileged position was predicated on either having nuclear medicine expertise, a medical license, or both. The fact that fMRI involved no inherent biohazard meant that it could now be deployed within less restricted environments, for example, within psychology departments of universities. In essence, fMRI democratized access to a powerful technology for investigating the living human brain, allowing a broad cross-section of academic disciplines to pursue new agendas. This, in my view, accounts for a virtual exponential rise in published neuroimaging output that, over the past 15 years, has been largely led by questions related to human cognition. Most people would agree that democracy is a good thing; equally, most people would agree that all things taken in excess should carry a health warning. The first applications of activation-based neuroimaging in the late 1980s involved the use of PET and utilized simple subtraction techniques based upon presenting alternating blocks of stimuli. In essence, this approach involved measuring brain activity in a condition of interest in one block and then subtracting activity associated with a carefully specified control condition acquired in a second block. This procedure was predicated on the idea of pure insertion of sequential cognitive processes and allowed, in principle, localization of discrete cognitive functions (Friston et al., 1996Friston K.J. Price C.J. Fletcher P. Moore C. Frackowiak R.S. Dolan R.J. The trouble with cognitive subtraction.Neuroimage. 1996; 4: 97-104Crossref PubMed Scopus (389) Google Scholar). Early examples of this methodology included identifying brain regions that process single words (Petersen et al., 1988Petersen S.E. Fox P.T. Posner M.I. Mintun M. Raichle M.E. Positron emission tomographic studies of the cortical anatomy of single-word processing.Nature. 1988; 331: 585-589Crossref PubMed Scopus (1942) Google Scholar, Posner et al., 1988Posner M.I. Petersen S.E. Fox P.T. Raichle M.E. Localization of cognitive operations in the human brain.Science. 1988; 240: 1627-1631Crossref PubMed Scopus (1018) Google Scholar) and the human homolog of V4 (Lueck et al., 1989Lueck C.J. Zeki S. Friston K.J. Deiber M.P. Cope P. Cunningham V.J. Lammertsma A.A. Kennard C. Frackowiak R.S. The colour centre in the cerebral cortex of man.Nature. 1989; 340: 386-389Crossref PubMed Scopus (313) Google Scholar) and V5 (Zeki et al., 1991Zeki S. Watson J. Lueck J. Friston K.J. Kennard C. Frackowiak R.S.J. A Direct Demonstration of Functional Specialization in Human Visual Cortex.J. Neurosci. 1991; 11: 641-649PubMed Google Scholar), areas specialized for visual color and motion processing, respectively. These so-called "block designs" also characterize early fMRI studies. Where PET measurements necessarily required long data collection sequences, such temporal inflexibility was overcome using fMRI. In the first instance, more flexible thinking on the part of experimental design provided new, more rigorous approaches that involved the implementation of parametric (Grafton et al., 1992Grafton S.T. Mazziotta J.C. Presty S. Friston K.J. Frackowiak R.S. Phelps M.E. Functional anatomy of human procedural learning determined with regional cerebral blood flow and PET.J. Neurosci. 1992; 12: 2542-2548PubMed Google Scholar) and factorial experimental designs (Friston et al., 1992Friston K.J. Frith C.D. Passingham R.E. Liddle P.F. Frackowiak R.S. Motor practice and neurophysiological adaptation in the cerebellum: a positron tomography study.Proc. Biol. Sci. 1992; 248: 223-228Crossref PubMed Scopus (200) Google Scholar). These provided a higher degree of experimental control and inference. Such developments coincided with a new class of questions, such as "how does the presence or absence of selective attention influence brain activity associated with processing some other factor?" 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This was initiated by the implementation of event-related fMRI, a procedure akin to measuring evoked responses in electrophysiology, and obviated the shortcomings of the less flexible blocked designs. Researchers were now able to capitalize on known physiological properties of neurons, such as their susceptibility to adaptation with repetition of an input, and, using this knowledge, to enhance both spatial and functional sensitivity. This latter approach, akin to repetition suppression, allowed detection of representations that might be instantiated within topographically overlapping neuronal networks. This new approach was applied to both low-level and high-level stimulus attributes (Tootell et al., 1998Tootell R.B. Hadjikhani N.K. Vanduffel W. Liu A.K. Mendola J.D. Sereno M.I. Dale A.M. Functional analysis of primary visual cortex (V1) in humans.Proc. Natl. Acad. Sci. USA. 1998; 95: 811-817Crossref PubMed Scopus (341) Google Scholar: Grill-Spector and Malach, 2001Grill-Spector K. 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One far-reaching impact of neuroimaging has been the extent to which investigators were now empowered to tackle issues and questions that were not reflected in classical psychological parsing of the mind, as might be found in standard textbooks of psychology. In this regard, the impact of neuroimaging has arguably been greatest in relation to topics that were either ignored in neuropsychology or were heretofore difficult to tackle experimentally. Two pertinent examples involve the growth of studies that address the biological underpinnings of consciousness and emotion, respectively. In studies of consciousness, neuroimaging provided the means to address disparate questions inconceivable without this new technology. These include how the exercise of "free will" engages discrete circuits (Frith and Dolan, 1996Frith C. Dolan R. The role of the prefrontal cortex in higher cognitive functions.Brain Res. Cogn. 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McInerney S.C. Lee M.B. Jenike M.A. Masked presentations of emotional facial expressions modulate amygdala activity without explicit knowledge.J. Neurosci. 1998; 18: 411-418PubMed Google Scholar), the expression of emotional learning and extinction (Buchel et al., 1998Buchel C. Morris J. Dolan R.J. Friston K.J. Brain systems mediating aversive conditioning: an event-related fMRI study.Neuron. 1998; 20: 947-957Abstract Full Text Full Text PDF PubMed Scopus (769) Google Scholar, LaBar et al., 1998LaBar K.S. Gatenby J.C. Gore J.C. LeDoux J.E. Phelps E.A. Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fMRI study.Neuron. 1998; 20: 937-945Abstract Full Text Full Text PDF PubMed Scopus (1064) Google Scholar), and how emotion impacts on perception (Noesselt et al., 2005Noesselt T. Driver J. Heinze H.J. Dolan R. Asymmetrical activation in the human brain during processing of fearful faces.Curr. 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Subcortical and cortical brain activity during the feeling of self-generated emotions.Nat. Neurosci. 2000; 3: 1049-1056Crossref PubMed Scopus (1472) Google Scholar) and enabled a description of how interoceptive states, for example, changes in peripheral autonomic status, are mapped in the brain (Critchley et al., 2004Critchley H.D. Wiens S. Rotshtein P. Ohman A. Dolan R.J. Neural systems supporting interoceptive awareness.Nat. Neurosci. 2004; 7: 189-195Crossref PubMed Scopus (2224) Google Scholar). Interestingly, the representation of interoceptive states in anterior insular cortex was subsequently shown to also provide a substrate that enables a person to represent the subjective feeling states of others as, for example, expressed in empathy for pain (Singer et al., 2004Singer T. Seymour B. O'Doherty J. Kaube H. Dolan R.J. Frith C.D. Empathy for pain involves the affective but not sensory components of pain.Science. 2004; 303: 1157-1162Crossref PubMed Scopus (2587) Google Scholar). Less than 20 years since its inception, the field of neuroimaging, using fMRI, has reached a high level of maturity and methodological sophistication. Neuroimaging now attracts interest not only from cognitive neuroscientists but also from a wide array of fields that lay outside those that might be thought to be concerned about the brain. Consequently, we have witnessed the emergence of a strong symbiosis between functional neuoroimaging and a range of other disciplines, in many instances constituting unlikely bedfellows, including genetics (Drabant et al., 2006Drabant E.M. Hariri A.R. Meyer-Lindenberg A. Munoz K.E. Mattay V.S. Kolachana B.S. Egan M.F. Weinberger D.R. Catechol O-methyltransferase val158met genotype and neural mechanisms related to affective arousal and regulation.Arch. Gen. Psychiatry. 2006; 63: 1396-1406Crossref PubMed Scopus (292) Google Scholar, Hariri et al., 2002Hariri A.R. Mattay V.S. Tessitore A. Kolachana B. Fera F. Goldman D. Egan M.F. Weinberger D.R. Serotonin transporter genetic variation and the response of the human amygdala.Science. 2002; 297: 400-403Crossref PubMed Scopus (1865) Google Scholar), economics (Camerer, 2003Camerer C.F. Psychology and economics. Strategizing in the brain.Science. 2003; 300: 1673-1675Crossref PubMed Scopus (123) Google Scholar, de Quervain et al., 2004de Quervain D.J. Fischbacher U. Treyer V. Schellhammer M. Schnyder U. Buck A. Fehr E. The neural basis of altruistic punishment.Science. 2004; 305: 1254-1258Crossref PubMed Scopus (1031) Google Scholar, King-Casas et al., 2005King-Casas B. Tomlin D. Anen C. Camerer C.F. Quartz S.R. Montague P.R. Getting to know you: reputation and trust in a two-person economic exchange.Science. 2005; 308: 78-83Crossref PubMed Scopus (817) Google Scholar), ethics (Hsu et al., 2008Hsu M. Anen C. Quartz S.R. The right and the good: distributive justice and neural encoding of equity and efficiency.Science. 2008; 320: 1092-1095Crossref PubMed Scopus (233) Google Scholar), and aesthetics (Winston et al., 2007Winston J.S. O'Doherty J. Kilner J.M. Perrett D.I. Dolan R.J. Brain systems for assessing facial attractiveness.Neuropsychologia. 2007; 45: 195-206Crossref PubMed Scopus (274) Google Scholar), to name a few. A repeatedly asked question over the past 20 years is what brain imaging has brought to neuroscience that was not already known. First, functional imaging realized what was never previously possible: namely, a characterization of the functional anatomy of the intact brain without the confound of pathology and the likely consequential plastic reorganization in response to disease or developmental abnormalities. Second, functional neuroimaging highlighted that even simple tasks engaged more widespread areas of the brain than would have been assumed from the lesion-deficit approach. This has led to a richer conceptualization of how brain function underpins cognition not only in terms of functional differentiation (localization) but also in terms of functional integration (distributed function). This latter characterization has motivated a new class of questions and methodological approaches that address how distributed brain regions interact during performance of a psychological task, as characterized in terms of functional connectivity (Fletcher et al., 1996Fletcher P.C. Frit