>> Historical and Physiological Foundations of Modern Neuroimaging

	Interview with Marcus Raichle, Washington University in St. Louis From Studying The Mind, VHS © 2003, W. W. Norton

How did we come to understand the relationship between physiology and mental activity?

William James, in his two-volume classic on the principles of psychology, published in 1890, has a section up front on the energetics of thinking. And in there he describes experiments by Angelo Mosso, an Italian experimentalist who had done all kinds of physiological experiments.

Anybody who has ever felt the soft spot on an infant's head realizes that it pulsates. And so there was a great question in those days as to what it was that caused the brain to pulsate, but there was some speculation that it had to do with blood circulation. Around this time Mosso came to study a peasant by the name of Bertino who had incurred an injury that left him with a permanent pulsating soft spot in his skull. One day while Mosso was using some elaborate gadget to record these pulsations, the church bells rang noon, and he noticed a sudden increase in pulsations over the cortex. Mosso asked Bertino if he felt that he should have said his mid-day prayers, and he said "yes" and up the pulsations went and then down again. So then, conducting what may have been the first cognitive activation experiment ever, he asked him to multiply 8 by 12. So Mosso poses the question and the pulsations go up and then down again, and then Bertino answers and up and down they go again. And from this he concluded that changes in circulation of the brain were related to cognition.

How does fMRI work?

The development of fRMI was again by-product of some interesting experimental issues and of people with the right ideas coming together at the right time. At the time, the general perception in the PET imaging world was that the reason that blood flow goes up when you think is because you need more oxygen. And people made this assumption because the brain is totally dependent on oxygen to burn glucose to provide energy. And it's a very big consumer. In fact, it consumes 20 percent of all the oxygen the body takes in and yet it's only 10 percent of the body's weight. So it was logical to assume that if you thought harder or if you moved your arms or you moved your legs that naturally you would increase the amount of oxygen that is used simply because you needed to burn more glucose to provide that extra energy for that hot thought you just had.

It was in pursuit of this that a colleague, Peter Fox, and I thought it would be very nice to just show that. And we were pretty sure that we knew the answer before we did the experiment, but we thought it would be nice to know, and then everybody would agree, and life would go on. But much to our great surprise when we looked at this, we found that even though blood flow went up and glucose consumption went up, the amount of oxygen used didn't.

This revealed that when you increase activity within the brain in a cognitive experiment, you increase blood flow and the amount of glucose that's used, but you don't increase the amount of oxygen. So the amount of oxygen delivered to the brain now exceeds what it normally uses, and as supply exceeds demand, you now simply have more oxygen in the area of brain that's doing something. Well, the main place that that oxygen resides in the brain if it's not being used is in the blood, hanging on to this big molecule of hemoglobin. And this realization was very important for the development of Functional Magnetic Resonance Imaging, which of course depends upon the magnetic field properties of the thing you're looking at.

In 1937 Linus Pauling had observed that the magnetic properties of this molecule hemoglobin, which is the carrier of oxygen around the body, are very dependent on how much oxygen it's carrying. So if it's carrying a lot of oxygen and you put it in a magnetic field, it doesn't do much to the magnetic field. But if it doesn't have much oxygen on it and you put it in a magnetic field, it disrupts the field. Seigi Ogawa, who had gotten his Ph.D. studying the magnetic properties of hemoglobin, knew well the observations of Linus Pauling, and was working with magnetic resonance imaging in animals. When he learned of our physiological observations, he deduced that it would be possible to detect the difference in oxygenation and relate that to changes in function. He then did a truly seminal experiment in which he simply looked at rats breathing room air and rats breathing 100 percent oxygen. In the rats breathing room air you could see these beautiful veins in the brain of the rat. And when the rat was breathing 100 percent oxygen, which filled up all the hemoglobin, the veins disappeared. He subsequently coined the term “blood oxygen level dependent signal” and suggested that this would be a way to examine functional activity in the human brain. And with that, functional magnetic resonance imaging was born, and it works. Now instead of having to inject an isotope into a vein as was needed in PET, we just use the intrinsic signal produced by the brain itself.