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Despite a promising beginning, including the seminal animal experimental observations of Roy and Sherrington (9), which suggested a link between brain circulation and metabolism, interest in this research virtually ceased during the first quarter of the twentieth century. Undoubtedly, this was due in part to a lack of tools sufficiently sophisticated to pursue this line of research. In addition, the work of Leonard Hill, Hunterian Professor of the Royal College of Surgeons in England, was very influential (19). His eminence as a physiologist overshadowed the inadequacy of his own experiments that led him to conclude that no relationship existed between brain function and brain circulation.

There was no serious challenge to Leonard Hill’s views until a remarkable clinical study was reported by John Fulton in the 1928 issue of the journal Brain (86). At the time of the report Fulton was a neurosurgery resident under Harvey Cushing at the Peter Bent Brigham Hospital in Boston. A patient presented to Cushing’s service with gradually decreasing vision caused by an arteriovenous malformation of the occipital cortex. Surgical removal of the malformation was attempted but unsuccessful, leaving the patient with a bony defect over the primary visual cortex. Fulton elicited a history of a cranial bruit audible to the patient whenever he engaged in a visual task. Based on this history Fulton pursued a detailed investigation of the behavior of the bruit that he could auscultate and record over occipital cortex. Remarkably consistent changes in the character of the bruit could be appreciated depending upon the visual activities of the patient. Although opening the eyes produced only modest increases in the intensity of the bruit, reading produced striking increases. The changes in cortical blood flow related to the complexity of the visual task and the attention of the subject to that task anticipated findings and concepts that have only recently been addressed with modern functional imaging techniques (20).

At the close of World War II, Seymour Kety and his colleagues opened the next chapter in studies of brain circulation and metabolism. Working with Lou Sokoloff and others, Kety developed the first quantitative methods for measuring whole brain blood flow and metabolism in humans. The introduction of an in vivo tissue autoradiographic measurement of regional blood flow in laboratory animals by Kety’s group (21, 22) provided the first glimpse of quantitative changes in blood flow in the brain related directly to brain function. Given the later importance of derivatives of this technique to functional brain imaging with both PET and functional MRI (fMRI) it is interesting to note the (dis)regard the developers had for this technique as a means of assessing brain functional organization. Quoting from the comments of William Landau to the members of the American Neurological Association meeting in Atlantic City (21): “Of course we recognize that this is a very secondhand way of determining physiological activity: it is rather like trying to measure what a factory does by measuring the intake of water and the output of sewage. This is only a problem of plumbing and only secondary inferences can be made about function. We would not suggest that this is a substitute for electrical recording in terms of easy evaluation of what is going on.” With the introduction of the deoxyglucose technique for the regional measurement of glucose metabolism in laboratory animals (23) and its later adaptation for PET (24), enthusiasm was much greater for the potential of such measurements to enhance our knowledge of brain function (1).

Soon after Kety and his colleagues introduced their quantitative methods for measuring whole brain blood flow and metabolism in humans, David Ingvar, Neils Lassen and their Scandinavian colleagues introduced methods applicable to humans that permitted regional blood flow measurements to be made by using scintillation detectors arrayed like a helmet over the head (25). They demonstrated directly in normal human subjects that blood flow changed regionally during changes in brain functional activity. The first study of functionally induced regional changes in blood flow by using these techniques in normal humans was actually reported by Ingvar and Risberg (26) at an early meeting on brain blood and metabolism and was greeted with cautious enthusiasm and a clear sense of its potential importance for studies of human brain function by Seymour Kety (27). However, despite many studies of functionally induced changes in regional cerebral blood that followed (1, 28), this approach was not embraced by most neuroscientists or cognitive scientists. It is interesting to note that this indifference was to disappear almost completely in the 1980s, a subject to which we will return shortly.

In 1973 Godfrey Hounsfield (29) introduced x-ray computed tomography, a technique based on principles presented in 1963 by Alan Cormack (30, 31). Overnight the way in which we looked at the human brain changed. Immediately, researchers envisioned another type of tomography, PET, which created in vivo autoradioagrams of brain function (32, 33). A new era of functional brain mapping began. The autoradiographic techniques for the measurement of blood flow (21, 22) and glucose metabolism (23) in laboratory animals could now be performed safely in humans (24, 34). In addition, quantitative techniques were developed (35, 36) and, importantly, validated (36, 37) for the measurement of oxygen consumption.

Soon it was realized that highly accurate measurements of brain function in humans could be performed with PET (38). Although this could be accomplished with either measurements of blood flow or metabolism (1), blood flow became the favored technique because it could be measured quickly (<1 min) by using an easily produced radiopharmaceutical (H215O) with a short half life (123 sec) that allowed many repeat measurements in the same subject.

The study of human cognition with PET was aided greatly by the involvement of cognitive psychologists in the 1980s whose experimental designs for dissecting human behaviors by using information-processing theory fit extremely well with the emerging functional brain imaging strategies (38). It may well have been the combination of cognitive science and systems neuroscience with brain imaging that lifted this work from a state of indifference and obscurity in the neuroscience community in the 1970s to its current role of prominence in cognitive neuroscience.

As a result of collaboration among neuroscientists, imaging scientists, and cognitive psychologists, a distinct behavioral strategy for the functional mapping of neuronal activity emerged. This strategy was based on a concept introduced by the Dutch physiologist Franciscus C.Donders in 1868 (reprinted in ref. 39). Donders proposed a general method to measure thought processes based on a simple logic. He subtracted the time needed to respond to a light (say, by pressing a key) from the time needed to respond to a particular color of light. He found that discriminating color required about 50 msec. In this way, Donders isolated and measured a mental process for the first time by subtracting a control state (i.e., responding to a light) from a task state (i.e., discriminating the color of the light). An example of the manner in which this strategy has been adopted for functional imaging is illustrated in Fig. 1.

One criticism of this approach has been that the time necessary to press a key after a decision to do so has been made is affected by the nature of the decision process itself. By implication, the nature of the processes underlying key press, in this example, may have been altered. Although this issue (known in cognitive science jargon as the assumption of pure insertion) has been the subject of continuing discussion in cognitive psychology, it finds its resolution in functional brain imaging, where changes in any process are directly signaled by changes in observable brain states. Events occurring in the brain are not hidden from the investigator as in the purely cognitive experiments. Careful analysis of the changes in the functional images reveals whether processes (e.g., specific cognitive decisions) can be added or removed without affecting ongoing processes (e.g., motor processes). Processing areas of the brain that become inactive during the course of a particular cognitive paradigm are illustrated in Fig. 2. By examining the images in Figs. 1 and 2 together, a more complete picture emerges of the changes taking place in the cognitive

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